17-63917348-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

LOC112268204 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GH1	NM_000515.5	c.615C>G	p.Ile205Met	missense_variant	5/5	ENST00000323322.10
LOC112268204	XR_002958148.2	n.341-249G>C		intron_variant, non_coding_transcript_variant
GH1	NM_022559.4	c.570C>G	p.Ile190Met	missense_variant	5/5
GH1	NM_022560.4	c.495C>G	p.Ile165Met	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10	c.615C>G	p.Ile205Met	missense_variant	5/5	1	NM_000515.5	P1

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

GnomAD3 exomes AF: 0.000418 AC: 105 AN: 251244 Hom.: 2 AF XY: 0.000523 AC XY: 71 AN XY: 135794

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 SAS exome AF: 0.000719

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

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000541

Gnomad4 OTH exome AF: 0.000497

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

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000474

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	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) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 01, 2022

Variant summary: GH1 c.615C>G (p.Ile205Met; aka. I179M) 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. The observed variant frequency is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in GH1 causing Idiopathic Growth Hormone Deficiency phenotype (6.3e-05), suggesting that the variant could be benign. The variant, c.615C>G, has been reported in the literature in two individuals affected with short stature (Lewis_2004 and Fritez_2015), 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.49	T;T;T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.077	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0070	.;.;B;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

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

Publications

LitVar

Other links and lift over

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