chr17-63917348-G-C

Position:

chr17-63917348-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.01

Variant links:

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 links:

LOC112268204 (HGNC:):

LOC112268204 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10 linkuse as main transcript	c.615C>G	p.Ile205Met	missense_variant	5/5	1	NM_000515.5	P1	P01241-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000523

AC XY:

AN XY:

135794

show subpopulations

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.:

Cov.:

AF XY:

0.000554

AC XY:

403

AN XY:

727164

show subpopulations

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:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.000442

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2018	- -

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

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

9.7

DANN

Benign

0.83

DEOGEN2

Uncertain

0.59

.;.;D;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.49

T;T;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.077

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.69

.;.;N;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.48

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over