rs863223310

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPM2PP3_StrongPP5_Moderate

The NM_000515.5(GH1):​c.291+2T>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GH1
NM_000515.5 splice_donor

Scores

1
3
3
Splicing: ADA: 1.000
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.42
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.18195719 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
PP5
Variant 17-63918015-A-G is Pathogenic according to our data. Variant chr17-63918015-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15980.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GH1NM_000515.5 linkuse as main transcriptc.291+2T>C splice_donor_variant ENST00000323322.10
GH1NM_022559.4 linkuse as main transcriptc.246+2T>C splice_donor_variant
GH1NM_022560.4 linkuse as main transcriptc.172-91T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GH1ENST00000323322.10 linkuse as main transcriptc.291+2T>C splice_donor_variant 1 NM_000515.5 P1P01241-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 16, 2018- -
Autosomal dominant isolated somatotropin deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2003- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Benign
0.90
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
D;D;D;D;D
GERP RS
2.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Benign
0.72
SpliceAI score (max)
0.85
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.85
Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863223310; hg19: chr17-61995375; API