rs695

Positions:

• chr17-63918839-T-A
• chr17-63918839-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000515.5(GH1):​c.-63A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 1,609,998 control chromosomes in the GnomAD database, including 8,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (952 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7458 hom.)
• Consequence: GH1 NM_000515.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.15

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]

ENSG00000285947 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-63918839-T-A is Benign according to our data. Variant chr17-63918839-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 369218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GH1	NM_000515.5	c.-63A>T		5_prime_UTR_variant	1/5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.-63A>T		5_prime_UTR_variant	1/5		NP_072053.1
GH1	NM_022560.4	c.-63A>T		5_prime_UTR_variant	1/4		NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10	c.-63A>T		5_prime_UTR_variant	1/5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.287-333A>T		intron_variant				ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15912 AN: 150964 Hom.: 954 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0901

GnomAD4 exome AF: 0.0970 AC: 141500 AN: 1458916 Hom.: 7458 Cov.: 37 AF XY: 0.0953 AC XY: 69163 AN XY: 725834

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.0521

Gnomad4 ASJ exome AF: 0.0793

Gnomad4 EAS exome AF: 0.0337

Gnomad4 SAS exome AF: 0.0381

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.0954

GnomAD4 genome AF: 0.105 AC: 15922 AN: 151082 Hom.: 952 Cov.: 32 AF XY: 0.103 AC XY: 7649 AN XY: 73904

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0766

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.0328

Gnomad4 SAS AF: 0.0355

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0891

Alfa AF: 0.0462 Hom.: 37

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Isolated congenital growth hormone deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs695; hg19: chr17-61996199; COSMIC: COSV60111381;