17-63917428-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_000515.5(GH1):c.535G>C(p.Asp179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.46

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13372788).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000204 (31/152278) while in subpopulation NFE AF= 0.000368 (25/68026). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 14 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GH1	NM_000515.5	c.535G>C	p.Asp179His	missense_variant	5/5	ENST00000323322.10
LOC112268204	XR_002958148.2	n.341-169C>G		intron_variant, non_coding_transcript_variant
GH1	NM_022559.4	c.490G>C	p.Asp164His	missense_variant	5/5
GH1	NM_022560.4	c.415G>C	p.Asp139His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10	c.535G>C	p.Asp179His	missense_variant	5/5	1	NM_000515.5	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251168 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135734

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000360 AC: 526 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 258 AN XY: 727144

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000444

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74468

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	Identified in the heterozygous state in one individual with partial IGHD, but segregation data is limited (de Graaff et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D153H); This variant is associated with the following publications: (PMID: 18785993) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2022	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. Experimental studies have shown that this missense change affects GH1 function (PMID: 18785993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 891323). This missense change has been observed in individual(s) with autosomal dominant growth hormone deficiency (PMID: 18785993). This variant is present in population databases (rs151243538, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 179 of the GH1 protein (p.Asp179His). -

Decreased response to growth hormone stimulation test Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	6.0
Dann	Benign	0.26
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	0.56	D;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.014, 0.0040	.;.;B;B
Vest4		0.15
MVP		0.65
MPC		0.16
ClinPred		0.024	T
GERP RS		-2.4
Varity_R		0.27
gMVP		0.45

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: rs151243538; hg19: chr17-61994788; COSMIC: COSV60110336; COSMIC: COSV60110336;