17-63918836-C-G

Variant names:

• chr17-63918836-C-G
• rs6175
• NM_000515.5:c.-60G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• isolated growth hormone deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type II

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type IB

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short stature due to growth hormone qualitative anomaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285947 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GH1	NM_000515.5	c.-60G>C		5_prime_UTR_variant	Exon 1 of 5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.-60G>C		5_prime_UTR_variant	Exon 1 of 5		NP_072053.1
GH1	NM_022560.4	c.-60G>C		5_prime_UTR_variant	Exon 1 of 4		NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10	c.-60G>C		5_prime_UTR_variant	Exon 1 of 5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.287-330G>C		intron_variant	Intron 4 of 7			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

African (AFR) AF: 0.188 AC: 6247 AN: 33242

American (AMR) AF: 0.0173 AC: 774 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 518 AN: 26126

East Asian (EAS) AF: 0.0130 AC: 517 AN: 39676

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86212

European-Finnish (FIN) AF: 0.00590 AC: 315 AN: 53416

Middle Eastern (MID) AF: 0.0181 AC: 104 AN: 5752

European-Non Finnish (NFE) AF: 0.00667 AC: 7401 AN: 1110132

Other (OTH) AF: 0.0188 AC: 1133 AN: 60296

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

African (AFR) AF: 0.179 AC: 7416 AN: 41350

American (AMR) AF: 0.0354 AC: 541 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.0185 AC: 96 AN: 5186

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4820

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00818 AC: 556 AN: 67954

Other (OTH) AF: 0.0408 AC: 86 AN: 2110

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

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Decreased response to growth hormone stimulation test Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.29
PromoterAI		-0.00050	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

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

Other links and lift over

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