20-36897960-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_015474.4(SAMHD1):​c.1609-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 7.16
Variant links:
Genes affected
SAMHD1 (HGNC:15925): (SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1) This gene may play a role in regulation of the innate immune response. The encoded protein is upregulated in response to viral infection and may be involved in mediation of tumor necrosis factor-alpha proinflammatory responses. Mutations in this gene have been associated with Aicardi-Goutieres syndrome. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.073365234 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 19, new splice context is: cgtttcacaacttctgccAGaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SAMHD1NM_015474.4 linkc.1609-1G>C splice_acceptor_variant, intron_variant Intron 14 of 15 ENST00000646673.2 NP_056289.2 Q9Y3Z3-1Q59H15
SAMHD1NM_001363729.2 linkc.1504-1G>C splice_acceptor_variant, intron_variant Intron 13 of 14 NP_001350658.1
SAMHD1NM_001363733.2 linkc.1609-1G>C splice_acceptor_variant, intron_variant Intron 14 of 15 NP_001350662.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SAMHD1ENST00000646673.2 linkc.1609-1G>C splice_acceptor_variant, intron_variant Intron 14 of 15 NM_015474.4 ENSP00000493536.2 Q9Y3Z3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251328
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461812
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 5 Pathogenic:1Uncertain:1Other:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 29, 2020This variant has been observed in individual(s) with Aicardi-Goutières syndrome (PMID: 19525956). ClinVar contains an entry for this variant (Variation ID: 126409). Studies have shown that this variant is associated with skipping of exon 15 but is expected to preserve the integrity of the reading-frame (PMID: 19525956). 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. This variant is present in population databases (rs515726143, ExAC 0.006%). This sequence change affects an acceptor splice site in intron 14 of the SAMHD1 gene. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2009- -
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
31
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
SpliceAI score (max)
0.94
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.94
Position offset: -1

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: rs515726143; hg19: chr20-35526363; API