17-63917495-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_000515.5(GH1):c.468T>C(p.Asp156=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,968 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (3 hom.)
• Consequence: GH1 NM_000515.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -3.80

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013378203).
• BP6: Variant 17-63917495-A-G is Benign according to our data. Variant chr17-63917495-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 891325.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-3.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000177 (27/152302) while in subpopulation EAS AF= 0.000966 (5/5176). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GH1	NM_000515.5	c.468T>C	p.Asp156=	synonymous_variant	5/5	ENST00000323322.10
LOC112268204	XR_002958148.2	n.341-102A>G		intron_variant, non_coding_transcript_variant
GH1	NM_022559.4	c.423T>C	p.Asp141=	synonymous_variant	5/5
GH1	NM_022560.4	c.348T>C	p.Asp116=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10	c.468T>C	p.Asp156=	synonymous_variant	5/5	1	NM_000515.5	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251168 Hom.: 1 AF XY: 0.000228 AC XY: 31 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461666 Hom.: 3 Cov.: 31 AF XY: 0.000166 AC XY: 121 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74482

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000263 Hom.: 1

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	GH1: BP4, BP7 -

Decreased response to growth hormone stimulation test Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.042
Dann	Benign	0.77
FATHMM_MKL	Benign	0.018	N
MetaRNN	Benign	0.013	T
MutationTaster	Benign	1.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0070	B
Vest4		0.18
MVP		0.76
GERP RS		-1.6

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: rs201849388; hg19: chr17-61994855;