17-63918836-C-G

Position:

• chr17-63918836-C-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.-60G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,611,500 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (724 hom., cov: 32)
  • Exomes 𝑓: 0.012 (697 hom.)
• Consequence: GH1 NM_000515.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.293

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=-0.79).
• BP6: Variant 17-63918836-C-G is Benign according to our data. Variant chr17-63918836-C-G is described in ClinVar as [Benign]. Clinvar id is 324462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GH1	NM_000515.5	c.-60G>C		5_prime_UTR_variant	1/5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.-60G>C		5_prime_UTR_variant	1/5		NP_072053.1
GH1	NM_022560.4	c.-60G>C		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.-60G>C		5_prime_UTR_variant	1/5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.287-330G>C		intron_variant				ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8814 AN: 151882 Hom.: 721 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00818

Gnomad OTH AF: 0.0412

GnomAD4 exome AF: 0.0118 AC: 17213 AN: 1459502 Hom.: 697 Cov.: 35 AF XY: 0.0109 AC XY: 7916 AN XY: 726126

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.0130

Gnomad4 SAS exome AF: 0.00237

Gnomad4 FIN exome AF: 0.00590

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0581 AC: 8836 AN: 151998 Hom.: 724 Cov.: 32 AF XY: 0.0568 AC XY: 4220 AN XY: 74332

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.00818

Gnomad4 OTH AF: 0.0408

Alfa AF: 0.00480 Hom.: 2

Bravo AF: 0.0655

ClinVar

Significance: 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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Decreased response to growth hormone stimulation test Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6175; hg19: chr17-61996196; COSMIC: COSV60110538; COSMIC: COSV60110538;