rs45595032

Variant names:

• chr20-36892872-T-C
• rs45595032
• NM_015474.4:c.*60A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_015474.4(SAMHD1):​c.*60A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,600,802 control chromosomes in the GnomAD database, including 39 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 0.0045 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (31 hom.)
• Consequence: SAMHD1 NM_015474.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.968
• Publications: 0 publications found

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]

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00447 (681/152310) while in subpopulation NFE AF = 0.00651 (443/68028). AF 95% confidence interval is 0.00601. There are 8 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMHD1	NM_015474.4	c.*60A>G		3_prime_UTR_variant	Exon 16 of 16	ENST00000646673.2	NP_056289.2
TLDC2	NM_080628.3	c.*28T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000217320.8	NP_542195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2	c.*60A>G		3_prime_UTR_variant	Exon 16 of 16		NM_015474.4	ENSP00000493536.2
TLDC2	ENST00000217320.8	c.*28T>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_080628.3	ENSP00000217320.3

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 682 AN: 152192 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00516 AC: 1285 AN: 249026 AF XY: 0.00523

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00763

Gnomad OTH exome AF: 0.00736

GnomAD4 exome AF: 0.00553 AC: 8016 AN: 1448492 Hom.: 31 Cov.: 27 AF XY: 0.00537 AC XY: 3871 AN XY: 721522

African (AFR) AF: 0.000844 AC: 28 AN: 33156

American (AMR) AF: 0.000313 AC: 14 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00141 AC: 121 AN: 86002

European-Finnish (FIN) AF: 0.0145 AC: 775 AN: 53416

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5740

European-Non Finnish (NFE) AF: 0.00619 AC: 6806 AN: 1099862

Other (OTH) AF: 0.00445 AC: 267 AN: 59934

GnomAD4 genome AF: 0.00447 AC: 681 AN: 152310 Hom.: 8 Cov.: 32 AF XY: 0.00485 AC XY: 361 AN XY: 74468

African (AFR) AF: 0.00111 AC: 46 AN: 41570

American (AMR) AF: 0.00118 AC: 18 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00651 AC: 443 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00513 Hom.: 3

Bravo AF: 0.00316

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SAMHD1: BS2; TLDC2: BS2 -

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

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.35
DANN	Benign	0.33
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs45595032; hg19: chr20-35521275;