rs9282699

Variant names:

• chr17-63918823-T-C
• rs9282699
• NM_000515.5:c.-47A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000515.5(GH1):​c.-47A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,612,702 control chromosomes in the GnomAD database, including 612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (65 hom., cov: 32)
  • Exomes 𝑓: 0.025 (547 hom.)
• Consequence: GH1 NM_000515.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.361
• 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=-0.84).
• BP6: Variant 17-63918823-T-C is Benign according to our data. Variant chr17-63918823-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 891386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.027 (4102/152150) while in subpopulation AFR AF = 0.0315 (1306/41470). AF 95% confidence interval is 0.0301. There are 65 homozygotes in GnomAd4. There are 1917 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 65 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5	c.-47A>G		5_prime_UTR_variant	Exon 1 of 5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.-47A>G		5_prime_UTR_variant	Exon 1 of 5		NP_072053.1
GH1	NM_022560.4	c.-47A>G		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.-47A>G		5_prime_UTR_variant	Exon 1 of 5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.287-317A>G		intron_variant	Intron 4 of 7			ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4103 AN: 152032 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0479

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0219 AC: 5492 AN: 250716 AF XY: 0.0220

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0405

Gnomad EAS exome AF: 0.0158

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0242

GnomAD4 exome AF: 0.0255 AC: 37228 AN: 1460552 Hom.: 547 Cov.: 35 AF XY: 0.0252 AC XY: 18320 AN XY: 726612

African (AFR) AF: 0.0313 AC: 1045 AN: 33424

American (AMR) AF: 0.0188 AC: 840 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0448 AC: 1171 AN: 26130

East Asian (EAS) AF: 0.00990 AC: 393 AN: 39690

South Asian (SAS) AF: 0.0158 AC: 1358 AN: 86220

European-Finnish (FIN) AF: 0.0118 AC: 632 AN: 53416

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5756

European-Non Finnish (NFE) AF: 0.0271 AC: 30127 AN: 1110898

Other (OTH) AF: 0.0255 AC: 1541 AN: 60328

GnomAD4 genome AF: 0.0270 AC: 4102 AN: 152150 Hom.: 65 Cov.: 32 AF XY: 0.0258 AC XY: 1917 AN XY: 74402

African (AFR) AF: 0.0315 AC: 1306 AN: 41470

American (AMR) AF: 0.0235 AC: 359 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0479 AC: 166 AN: 3468

East Asian (EAS) AF: 0.0150 AC: 78 AN: 5186

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4824

European-Finnish (FIN) AF: 0.0114 AC: 121 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0280 AC: 1901 AN: 67976

Other (OTH) AF: 0.0209 AC: 44 AN: 2108

Alfa AF: 0.0183 Hom.: 6

Bravo AF: 0.0289

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Decreased response to growth hormone stimulation test Benign:1

Jan 18, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.6
DANN	Benign	0.66
PhyloP100		0.36
PromoterAI		-0.0018	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs9282699; hg19: chr17-61996183;