17-63919006-A-G

Variant names:

• chr17-63919006-A-G
• rs2727338
• ENST00000647774.1:c.287-500T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000647774.1(ENSG00000285947):​c.287-500T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 152,304 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.024 (52 hom., cov: 33)
• Consequence: ENSG00000285947 ENST00000647774.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.521
• Publications: 3 publications found

Genes affected

ENSG00000285947 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0237 (3602/152304) while in subpopulation NFE AF = 0.0349 (2371/68010). AF 95% confidence interval is 0.0337. There are 52 homozygotes in GnomAd4. There are 1735 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647774.1. 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.-230T>C		upstream_gene	N/A	NP_000506.2
	GH1	NM_022559.4		c.-230T>C		upstream_gene	N/A	NP_072053.1
	GH1	NM_022560.4		c.-230T>C		upstream_gene	N/A	NP_072054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285947	ENST00000647774.1		c.287-500T>C		intron	N/A	ENSP00000497443.1
	GH1	ENST00000323322.10	TSL:1 MANE Select	c.-230T>C		upstream_gene	N/A	ENSP00000312673.5
	GH1	ENST00000458650.6	TSL:1	c.-230T>C		upstream_gene	N/A	ENSP00000408486.2

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3598 AN: 152186 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.00721

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0519

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0124

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0237 AC: 3602 AN: 152304 Hom.: 52 Cov.: 33 AF XY: 0.0233 AC XY: 1735 AN XY: 74472

African (AFR) AF: 0.00729 AC: 303 AN: 41570

American (AMR) AF: 0.0121 AC: 185 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.0519 AC: 551 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2371 AN: 68010

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0152 Hom.: 7

Bravo AF: 0.0206

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.0
DANN	Benign	0.72
PhyloP100		0.52
PromoterAI		0.019	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2727338; hg19: chr17-61996366;