rs138927042

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_015474.4(SAMHD1):c.*71C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,584,406 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 45 hom. )

Consequence

SAMHD1
NM_015474.4 3_prime_UTR

Scores

Splicing: ADA: 0.9999

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.640

Publications

4 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 links:

TLDC2 (HGNC:16112): (TBC/LysM-associated domain containing 2) Predicted to be involved in response to oxidative stress. Predicted to act upstream of or within negative regulation of oxidative stress-induced neuron death. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TLDC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 20-36892861-G-T is Benign according to our data. Variant chr20-36892861-G-T is described in ClinVar as [Benign]. Clinvar id is 338337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00292 (445/152266) while in subpopulation SAS AF = 0.0195 (94/4828). AF 95% confidence interval is 0.0163. There are 2 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMHD1	NM_015474.4 link	c.*71C>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000646673.2	NP_056289.2	Q9Y3Z3-1Q59H15
TLDC2	NM_080628.3 link	c.*18-1G>T		splice_acceptor_variant, intron_variant	Intron 6 of 6	ENST00000217320.8	NP_542195.1	A0PJX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2 link	c.*71C>A		3_prime_UTR_variant	Exon 16 of 16		NM_015474.4	ENSP00000493536.2		Q9Y3Z3-1
TLDC2	ENST00000217320.8 link	c.*18-1G>T		splice_acceptor_variant, intron_variant	Intron 6 of 6	1	NM_080628.3	ENSP00000217320.3		A0PJX2

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

443

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0190

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00387

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00462

AC:

1151

AN:

248944

AF XY:

0.00569

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00375

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00481

AC:

6887

AN:

1432140

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

3827

AN XY:

714356

show subpopulations

African (AFR)

AF:

0.000731

AC:

AN:

32824

American (AMR)

AF:

0.00161

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00289

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.0215

AC:

1845

AN:

85668

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00422

AC:

4577

AN:

1084912

Other (OTH)

AF:

0.00399

AC:

237

AN:

59432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

340

680

1019

1359

1699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00292

AC:

445

AN:

152266

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

217

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41560

American (AMR)

AF:

0.00118

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0195

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00387

AC:

263

AN:

68022

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00353

Hom.:

Bravo

AF:

0.00261

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00545

AC:

ExAC

AF:

0.00437

AC:

531

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00504

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 19, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chilblain lupus 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aicardi-Goutieres syndrome 5

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.79

Eigen

Uncertain

0.32

Eigen_PC

Benign

-0.033

FATHMM_MKL

Benign

0.22

PhyloP100

0.64

GERP RS

3.6

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.37

Position offset: 1

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

Publications

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rs138927042

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over