17-63918839-T-G

Variant names:

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

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>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 0.016 in 1,610,988 control chromosomes in the GnomAD database, including 1,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (722 hom., cov: 32)
  • Exomes 𝑓: 0.012 (687 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=-0.74).
• BP6: Variant 17-63918839-T-G is Benign according to our data. Variant chr17-63918839-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 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>C		5_prime_UTR	Exon 1 of 5	NP_000506.2
	GH1	NM_022559.4		c.-63A>C		5_prime_UTR	Exon 1 of 5	NP_072053.1
	GH1	NM_022560.4		c.-63A>C		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>C		5_prime_UTR	Exon 1 of 5	ENSP00000312673.5
	ENSG00000285947	ENST00000647774.1		c.287-333A>C		intron	N/A	ENSP00000497443.1
	GH1	ENST00000458650.6	TSL:1	c.-63A>C		upstream_gene	N/A	ENSP00000408486.2

Frequencies

GnomAD3 genomes AF: 0.0568 AC: 8611 AN: 151644 Hom.: 719 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00820

Gnomad OTH AF: 0.0408

GnomAD4 exome AF: 0.0118 AC: 17155 AN: 1459226 Hom.: 687 Cov.: 37 AF XY: 0.0109 AC XY: 7893 AN XY: 725990

African (AFR) AF: 0.188 AC: 6255 AN: 33254

American (AMR) AF: 0.0151 AC: 673 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 516 AN: 26126

East Asian (EAS) AF: 0.0130 AC: 517 AN: 39678

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86206

European-Finnish (FIN) AF: 0.00590 AC: 315 AN: 53412

Middle Eastern (MID) AF: 0.0181 AC: 104 AN: 5752

European-Non Finnish (NFE) AF: 0.00671 AC: 7442 AN: 1109874

Other (OTH) AF: 0.0187 AC: 1129 AN: 60284

GnomAD4 genome AF: 0.0569 AC: 8634 AN: 151762 Hom.: 722 Cov.: 32 AF XY: 0.0548 AC XY: 4064 AN XY: 74222

African (AFR) AF: 0.180 AC: 7416 AN: 41182

American (AMR) AF: 0.0222 AC: 338 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.0185 AC: 96 AN: 5180

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00820 AC: 557 AN: 67940

Other (OTH) AF: 0.0404 AC: 85 AN: 2104

Alfa AF: 0.00316 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	-0.74
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		1.1
PromoterAI		0.013	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: COSV60110543;