chr20-36898455-C-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_015474.4(SAMHD1):āc.1593G>Cā(p.Arg531Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,613,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_015474.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SAMHD1 | NM_015474.4 | c.1593G>C | p.Arg531Ser | missense_variant | 14/16 | ENST00000646673.2 | |
SAMHD1 | NM_001363733.2 | c.1593G>C | p.Arg531Ser | missense_variant | 14/16 | ||
SAMHD1 | NM_001363729.2 | c.1504-496G>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SAMHD1 | ENST00000646673.2 | c.1593G>C | p.Arg531Ser | missense_variant | 14/16 | NM_015474.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000375 AC: 57AN: 152060Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000485 AC: 122AN: 251410Hom.: 0 AF XY: 0.000522 AC XY: 71AN XY: 135894
GnomAD4 exome AF: 0.000611 AC: 893AN: 1460994Hom.: 0 Cov.: 30 AF XY: 0.000587 AC XY: 427AN XY: 726834
GnomAD4 genome AF: 0.000375 AC: 57AN: 152060Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20AN XY: 74278
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 05, 2022 | - - |
Aicardi-Goutieres syndrome 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 531 of the SAMHD1 protein (p.Arg531Ser). This variant is present in population databases (rs145735112, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SAMHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 338342). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SAMHD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Aicardi Goutieres syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2022 | The c.1593G>C (p.R531S) alteration is located in exon 14 (coding exon 14) of the SAMHD1 gene. This alteration results from a G to C substitution at nucleotide position 1593, causing the arginine (R) at amino acid position 531 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2024 | Variant summary: SAMHD1 c.1593G>C (p.Arg531Ser) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 251410 control chromosomes. The observed variant frequency is approximately 1-fold of the estimated maximal expected allele frequency for a pathogenic variant in SAMHD1 causing Aicardi Goutieres Syndrome phenotype (0.0004), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1593G>C in individuals affected with Aicardi Goutieres Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 338342). Based on the evidence outlined above, the variant was classified as likely benign. - |
Chilblain lupus 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at