dbSNP rs2727338: ENSG00000285947:c.287-500T>C (chr17-63919006-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.521

Publications

3 publications found

Variant links:

Genes affected

ENSG00000285947 (HGNC:):

ENSG00000285947 links:

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

GH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
GH1	NM_000515.5 link	c.-230T>C	upstream_gene_variant	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4 link	c.-230T>C	upstream_gene_variant		NP_072053.1
GH1	NM_022560.4 link	c.-230T>C	upstream_gene_variant		NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285947	ENST00000647774.1 link	c.287-500T>C		intron_variant	Intron 4 of 7			ENSP00000497443.1
GH1	ENST00000323322.10 link	c.-230T>C		upstream_gene_variant		1	NM_000515.5	ENSP00000312673.5

Frequencies

GnomAD3 genomes

AF:

0.0236

AC:

3598

AN:

152186

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.0233

AC XY:

1735

AN XY:

74472

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5186

South Asian (SAS)

AF:

0.00911

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0519

AC:

551

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0349

AC:

2371

AN:

68010

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

174

349

523

698

872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0206

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

8.0

(source)

DANN

Benign

0.72

PhyloP100

0.52

PromoterAI

0.019

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over