17-63917348-G-C

Variant names:

• chr17-63917348-G-C
• rs148474991
• NM_000515.5:c.615C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000515.5(GH1):​c.615C>G​(p.Ile205Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,614,012 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (6 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.01
• Publications: 8 publications found

Genes affected

GH1 (HGNC:4261): (growth hormone 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature. [provided by RefSeq, Jul 2008]

GH1 Gene-Disease associations (from GenCC):

• isolated growth hormone deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type II

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type IB

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short stature due to growth hormone qualitative anomaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285947 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07723981).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000394 (60/152288) while in subpopulation AFR AF = 0.00077 (32/41572). AF 95% confidence interval is 0.000559. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000515.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	NM_000515.5	MANE Select	c.615C>G	p.Ile205Met	missense	Exon 5 of 5	NP_000506.2
	GH1	NM_022559.4		c.570C>G	p.Ile190Met	missense	Exon 5 of 5	NP_072053.1
	GH1	NM_022560.4		c.495C>G	p.Ile165Met	missense	Exon 4 of 4	NP_072054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	ENST00000323322.10	TSL:1 MANE Select	c.615C>G	p.Ile205Met	missense	Exon 5 of 5	ENSP00000312673.5
	ENSG00000285947	ENST00000647774.1		c.891C>G	p.Ile297Met	missense	Exon 8 of 8	ENSP00000497443.1
	GH1	ENST00000458650.6	TSL:1	c.570C>G	p.Ile190Met	missense	Exon 5 of 5	ENSP00000408486.2

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000418 AC: 105 AN: 251244 AF XY: 0.000523

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000524 AC: 766 AN: 1461724 Hom.: 6 Cov.: 31 AF XY: 0.000554 AC XY: 403 AN XY: 727164

African (AFR) AF: 0.00122 AC: 41 AN: 33472

American (AMR) AF: 0.000447 AC: 20 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.000541 AC: 602 AN: 1111898

Other (OTH) AF: 0.000497 AC: 30 AN: 60378

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74468

African (AFR) AF: 0.000770 AC: 32 AN: 41572

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000436

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Nov 29, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a decreased ability to activate ERK, but show normal JAK/STAT pathway activation, normal secretion, and normal binding characteristics (Lewis et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25557026, 28498917, 15001589)

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 205 of the GH1 protein (p.Ile205Met). This variant is present in population databases (rs148474991, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of GH1-related conditions (PMID: 15001589, 25557026). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ile179Met. ClinVar contains an entry for this variant (Variation ID: 500833). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects GH1 function (PMID: 15001589). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Apr 30, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Sep 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GH1 c.615C>G (p.Ile205Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 251244 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GH1 causing Idiopathic Growth Hormone Deficiency (0.00042 vs 0.011), allowing no conclusion about variant significance. The variant, c.615C>G, has been reported in the literature in individuals affected with GH1-related disorders (Lewis_2004, Fritez_2015, Kirkgoz_2023), however, in one of the reported families the variant did not cosegregate with the phenotype (Lewis_2004). These data do not allow clear conclusions about variant significance. One of these publications also reported experimental evidence evaluating an impact on protein function, demonstrating normal secretion, and receptor binding with normal JAK/STAT pathway activation for the variant protein, however, the activation of ERK pathway was reduced to about half (Lewis_2004). The impaired ability to activate ERK does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 2014261, 25557026, 10462528, 34426522, 37948564, 15001589, 28498917, 18488018, 34091447). ClinVar contains an entry for this variant (Variation ID: 500833). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	9.7
DANN	Benign	0.83
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.56
Sift	Benign	0.26	T
Sift4G	Benign	0.24	T
Polyphen		0.0070	B
Vest4		0.48
MVP		0.69
MPC		0.13
ClinPred		0.0094	T
GERP RS		-1.0
Varity_R		0.65
gMVP		0.46
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148474991; hg19: chr17-61994708; COSMIC: COSV60112201; COSMIC: COSV60112201;