Genetic Variant SAMHD1:p.Gln465* (chr20-36905381-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_015474.4(SAMHD1):c.1393C>T(p.Gln465*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.13

Publications

1 publications found

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]

SAMHD1 Gene-Disease associations (from GenCC):

Aicardi-Goutieres syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
SAMHD1-related type 1 interferonopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Moyamoya disease
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
Aicardi-Goutieres syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial chilblain lupus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
chilblain lupus 2
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
chilblain lupus
Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

SAMHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015474.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SAMHD1	NM_015474.4	MANE Select	c.1393C>T	p.Gln465*	stop_gained	Exon 12 of 16	NP_056289.2
SAMHD1	NM_001363729.2		c.1393C>T	p.Gln465*	stop_gained	Exon 12 of 15	NP_001350658.1	Q9Y3Z3-4
SAMHD1	NM_001363733.2		c.1393C>T	p.Gln465*	stop_gained	Exon 12 of 16	NP_001350662.1	A0A2R8YCS7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SAMHD1	ENST00000646673.2	MANE Select	c.1393C>T	p.Gln465*	stop_gained	Exon 12 of 16	ENSP00000493536.2	Q9Y3Z3-1
SAMHD1	ENST00000262878.5	TSL:1	c.1393C>T	p.Gln465*	stop_gained	Exon 12 of 15	ENSP00000262878.5	Q9Y3Z3-4
SAMHD1	ENST00000866371.1		c.1531C>T	p.Gln511*	stop_gained	Exon 13 of 17	ENSP00000536430.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111958

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Benign

0.83

Eigen

Benign

-0.75

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

PhyloP100

-2.1

Vest4

0.94

GERP RS

-9.4

PromoterAI

-0.030

Neutral

(source)

Mutation Taster

=4/196

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over