17-63917337-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000515.5(GH1):c.626G>A(p.Arg209His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
GH1
NM_000515.5 missense
NM_000515.5 missense
Scores
6
7
4
Clinical Significance
Conservation
PhyloP100: 5.17
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 17-63917337-C-T is Pathogenic according to our data. Variant chr17-63917337-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GH1 | NM_000515.5 | c.626G>A | p.Arg209His | missense_variant | 5/5 | ENST00000323322.10 | |
LOC112268204 | XR_002958148.2 | n.341-260C>T | intron_variant, non_coding_transcript_variant | ||||
GH1 | NM_022559.4 | c.581G>A | p.Arg194His | missense_variant | 5/5 | ||
GH1 | NM_022560.4 | c.506G>A | p.Arg169His | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GH1 | ENST00000323322.10 | c.626G>A | p.Arg209His | missense_variant | 5/5 | 1 | NM_000515.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461742Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727174
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal dominant isolated somatotropin deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2007 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital | Feb 01, 2024 | - - |
Likely pathogenic, no assertion criteria provided | research | Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | May 31, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 03, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 209 of the GH1 protein (p.Arg209His). This variant is present in population databases (rs137853223, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal dominant growth hormone deficiency (PMID: 17785368, 29739035, 33729509, 34006472, 34589056). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg183His. ClinVar contains an entry for this variant (Variation ID: 15983). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 08, 2019 | The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected individuals from multiple families. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
T;T;T;T
Polyphen
0.41, 0.87
.;.;B;P
Vest4
MutPred
0.96
.;.;Gain of glycosylation at S214 (P = 0.0589);.;
MVP
MPC
0.14
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at