rs695

Variant names:

• chr17-63918839-T-A
• rs695
• NM_000515.5:c.-63A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-63918839-T-A
• chr17-63918839-T-C
• chr17-63918839-T-G

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.-63A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 1,609,998 control chromosomes in the GnomAD database, including 8,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (952 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7458 hom.)
• Consequence: GH1 NM_000515.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.15
• Publications: 12 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=-0.69).
• BP6: Variant 17-63918839-T-A is Benign according to our data. Variant chr17-63918839-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000515.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	NM_000515.5	MANE Select	c.-63A>T		5_prime_UTR	Exon 1 of 5	NP_000506.2
	GH1	NM_022559.4		c.-63A>T		5_prime_UTR	Exon 1 of 5	NP_072053.1
	GH1	NM_022560.4		c.-63A>T		5_prime_UTR	Exon 1 of 4	NP_072054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	ENST00000323322.10	TSL:1 MANE Select	c.-63A>T		5_prime_UTR	Exon 1 of 5	ENSP00000312673.5
	ENSG00000285947	ENST00000647774.1		c.287-333A>T		intron	N/A	ENSP00000497443.1
	GH1	ENST00000458650.6	TSL:1	c.-63A>T		upstream_gene	N/A	ENSP00000408486.2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15912 AN: 150964 Hom.: 954 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0901

GnomAD4 exome AF: 0.0970 AC: 141500 AN: 1458916 Hom.: 7458 Cov.: 37 AF XY: 0.0953 AC XY: 69163 AN XY: 725834

African (AFR) AF: 0.134 AC: 4431 AN: 33088

American (AMR) AF: 0.0521 AC: 2326 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0793 AC: 2072 AN: 26128

East Asian (EAS) AF: 0.0337 AC: 1337 AN: 39692

South Asian (SAS) AF: 0.0381 AC: 3285 AN: 86210

European-Finnish (FIN) AF: 0.122 AC: 6526 AN: 53406

Middle Eastern (MID) AF: 0.0717 AC: 413 AN: 5758

European-Non Finnish (NFE) AF: 0.104 AC: 115363 AN: 1109730

Other (OTH) AF: 0.0954 AC: 5747 AN: 60240

GnomAD4 genome AF: 0.105 AC: 15922 AN: 151082 Hom.: 952 Cov.: 32 AF XY: 0.103 AC XY: 7649 AN XY: 73904

African (AFR) AF: 0.128 AC: 5195 AN: 40524

American (AMR) AF: 0.0766 AC: 1166 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3470

East Asian (EAS) AF: 0.0328 AC: 170 AN: 5178

South Asian (SAS) AF: 0.0355 AC: 171 AN: 4822

European-Finnish (FIN) AF: 0.123 AC: 1309 AN: 10600

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.108 AC: 7325 AN: 67966

Other (OTH) AF: 0.0891 AC: 187 AN: 2098

Alfa AF: 0.0462 Hom.: 37

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Isolated congenital growth hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		1.1
PromoterAI		-0.020	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs695; hg19: chr17-61996199; COSMIC: COSV60111381;