rs6172

Positions:

• chr17-63918814-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000515.5(GH1):​c.-38A>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 0.0237 in 1,613,064 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (42 hom., cov: 32)
  • Exomes 𝑓: 0.024 (506 hom.)
• Consequence: GH1 NM_000515.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.334

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=-0.87).
• BP6: Variant 17-63918814-T-G is Benign according to our data. Variant chr17-63918814-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 891384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3270/152178) while in subpopulation NFE AF= 0.0267 (1818/67988). AF 95% confidence interval is 0.0257. There are 42 homozygotes in gnomad4. There are 1541 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GH1	NM_000515.5	c.-38A>C		5_prime_UTR_variant	1/5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.-38A>C		5_prime_UTR_variant	1/5		NP_072053.1
GH1	NM_022560.4	c.-38A>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.-38A>C		5_prime_UTR_variant	1/5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.287-308A>C		intron_variant				ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3262 AN: 152060 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0197 AC: 4953 AN: 250918 Hom.: 70 AF XY: 0.0199 AC XY: 2701 AN XY: 135628

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0377

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.0146

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0229

GnomAD4 exome AF: 0.0240 AC: 35033 AN: 1460886 Hom.: 506 Cov.: 35 AF XY: 0.0238 AC XY: 17274 AN XY: 726764

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0208

Gnomad4 ASJ exome AF: 0.0413

Gnomad4 EAS exome AF: 0.00204

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.0260

Gnomad4 OTH exome AF: 0.0233

GnomAD4 genome AF: 0.0215 AC: 3270 AN: 152178 Hom.: 42 Cov.: 32 AF XY: 0.0207 AC XY: 1541 AN XY: 74430

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0267

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0232 Hom.: 4

Bravo AF: 0.0229

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	See Variant Classification Assertion Criteria. -
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 18, 2018

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.56

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: rs6172; hg19: chr17-61996174;