rs6173

chr17-63918780-A-Cchr17-63918780-A-Gchr17-63918780-A-T

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.-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:4
• Conservation: PhyloP100: 0.0460

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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/exons	MANE	UniProt
GH1	NM_000515.5	c.-4T>G		5_prime_UTR_variant	1/5	ENST00000323322.10
GH1	NM_022559.4	c.-4T>G		5_prime_UTR_variant	1/5
GH1	NM_022560.4	c.-4T>G		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10	c.-4T>G		5_prime_UTR_variant	1/5	1	NM_000515.5	P1

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

GnomAD3 exomes AF: 0.0360 AC: 8968 AN: 249454 Hom.: 254 AF XY: 0.0350 AC XY: 4720 AN XY: 134946

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 SAS exome AF: 0.0241

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

Gnomad4 AFR exome AF: 0.0887

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.00831

Gnomad4 SAS exome AF: 0.0244

Gnomad4 FIN exome AF: 0.0304

Gnomad4 NFE exome AF: 0.0427

Gnomad4 OTH exome AF: 0.0404

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

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0352

Gnomad4 ASJ AF: 0.0254

Gnomad4 EAS AF: 0.00926

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0427

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0308 Hom.: 35

Bravo AF: 0.0581

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant isolated somatotropin deficiency;C0342573:Ateleiotic dwarfism;C1849779:Short stature due to growth hormone qualitative anomaly;C2748571:Isolated growth hormone deficiency type IB Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 29, 2017

- -

GH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 15, 2018

- -

Decreased response to growth hormone stimulation test Benign:1

Likely 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 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

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: rs6173; hg19: chr17-61996140;