Genetic Variant SAMHD1:c.1746+863T>C (chr20-36896959-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015474.4(SAMHD1):c.1746+863T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 151,834 control chromosomes in the GnomAD database, including 24,598 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.54 ( 24598 hom., cov: 31)

Consequence

SAMHD1
NM_015474.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.17

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
SAMHD1	NM_015474.4	MANE Select	c.1746+863T>C	intron	N/A	NP_056289.2
SAMHD1	NM_001363729.2		c.1641+863T>C	intron	N/A	NP_001350658.1	Q9Y3Z3-4
SAMHD1	NM_001363733.2		c.1746+863T>C	intron	N/A	NP_001350662.1	A0A2R8YCS7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SAMHD1	ENST00000646673.2	MANE Select	c.1746+863T>C	intron	N/A	ENSP00000493536.2	Q9Y3Z3-1
SAMHD1	ENST00000262878.5	TSL:1	c.1641+863T>C	intron	N/A	ENSP00000262878.5	Q9Y3Z3-4
SAMHD1	ENST00000866371.1		c.1884+863T>C	intron	N/A	ENSP00000536430.1

Frequencies

GnomAD3 genomes

AF:

0.545

AC:

82721

AN:

151716

Hom.:

24587

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.522

Gnomad ASJ

AF:

0.625

Gnomad EAS

AF:

0.543

Gnomad SAS

AF:

0.740

Gnomad FIN

AF:

0.576

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.673

Gnomad OTH

AF:

0.560

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.545

AC:

82740

AN:

151834

Hom.:

24598

Cov.:

AF XY:

0.546

AC XY:

40514

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.302

AC:

12486

AN:

41382

American (AMR)

AF:

0.521

AC:

7949

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.625

AC:

2170

AN:

3472

East Asian (EAS)

AF:

0.543

AC:

2809

AN:

5170

South Asian (SAS)

AF:

0.740

AC:

3559

AN:

4808

European-Finnish (FIN)

AF:

0.576

AC:

6043

AN:

10494

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.673

AC:

45724

AN:

67952

Other (OTH)

AF:

0.563

AC:

1184

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1721

3442

5162

6883

8604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.630

Hom.:

21944

Bravo

AF:

0.523

Asia WGS

AF:

0.620

AC:

2155

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.2

(source)

DANN

Benign

0.80

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over