rs6173

Variant names:

• chr17-63918780-A-C
• rs6173
• NM_000515.5:c.-4T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-63918780-A-C
• chr17-63918780-A-G
• chr17-63918780-A-T

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.-4T>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 0.0417 in 1,606,548 control chromosomes in the GnomAD database, including 1,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (335 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1496 hom.)
• Consequence: GH1 NM_000515.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0460
• Publications: 9 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=-0.85).
• BP6: Variant 17-63918780-A-C is Benign according to our data. Variant chr17-63918780-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 324460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5	c.-4T>G		5_prime_UTR_variant	Exon 1 of 5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.-4T>G		5_prime_UTR_variant	Exon 1 of 5		NP_072053.1
GH1	NM_022560.4	c.-4T>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.-4T>G		5_prime_UTR_variant	Exon 1 of 5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.287-274T>G		intron_variant	Intron 4 of 7			ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8328 AN: 152082 Hom.: 335 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0383

GnomAD2 exomes AF: 0.0360 AC: 8968 AN: 249454 AF XY: 0.0350

Gnomad AFR exome AF: 0.0846

Gnomad AMR exome AF: 0.0268

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0403 AC: 58640 AN: 1454348 Hom.: 1496 Cov.: 35 AF XY: 0.0394 AC XY: 28508 AN XY: 723706

African (AFR) AF: 0.0887 AC: 2851 AN: 32124

American (AMR) AF: 0.0269 AC: 1197 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 585 AN: 26066

East Asian (EAS) AF: 0.00831 AC: 330 AN: 39690

South Asian (SAS) AF: 0.0244 AC: 2102 AN: 86134

European-Finnish (FIN) AF: 0.0304 AC: 1623 AN: 53420

Middle Eastern (MID) AF: 0.0398 AC: 228 AN: 5726

European-Non Finnish (NFE) AF: 0.0427 AC: 47294 AN: 1106534

Other (OTH) AF: 0.0404 AC: 2430 AN: 60084

GnomAD4 genome AF: 0.0548 AC: 8338 AN: 152200 Hom.: 335 Cov.: 32 AF XY: 0.0528 AC XY: 3932 AN XY: 74430

African (AFR) AF: 0.103 AC: 4265 AN: 41486

American (AMR) AF: 0.0352 AC: 538 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3470

East Asian (EAS) AF: 0.00926 AC: 48 AN: 5182

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4832

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0427 AC: 2904 AN: 67994

Other (OTH) AF: 0.0379 AC: 80 AN: 2110

Alfa AF: 0.0308 Hom.: 35

Bravo AF: 0.0581

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Apr 06, 2022

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GH1-related disorder Benign:1

May 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Decreased response to growth hormone stimulation test Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.2
DANN	Benign	0.63
PhyloP100		0.046
PromoterAI		-0.0080	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6173; hg19: chr17-61996140;