20-36892644-T-C

Position:

• chr20-36892644-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015474.4(SAMHD1):​c.*288A>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 0.00244 in 415,224 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: SAMHD1 NM_015474.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.847

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 20-36892644-T-C is Benign according to our data. Variant chr20-36892644-T-C is described in ClinVar as [Benign]. Clinvar id is 338334.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00465 (706/151770) while in subpopulation AFR AF= 0.0138 (569/41374). AF 95% confidence interval is 0.0128. There are 3 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMHD1	NM_015474.4	c.*288A>G		3_prime_UTR_variant	16/16	ENST00000646673.2
TLDC2	NM_080628.3	c.*18-218T>C		intron_variant		ENST00000217320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMHD1	ENST00000646673.2	c.*288A>G		3_prime_UTR_variant	16/16		NM_015474.4	P1
TLDC2	ENST00000217320.8	c.*18-218T>C		intron_variant		1	NM_080628.3	P1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 705 AN: 151652 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00579

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.00576

GnomAD4 exome AF: 0.00116 AC: 306 AN: 263454 Hom.: 0 Cov.: 4 AF XY: 0.00104 AC XY: 148 AN XY: 141972

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.00497

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000548

Gnomad4 FIN exome AF: 0.000390

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00465 AC: 706 AN: 151770 Hom.: 3 Cov.: 32 AF XY: 0.00428 AC XY: 317 AN XY: 74140

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00578

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000486

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00387 Hom.: 1

Bravo AF: 0.00512

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Chilblain lupus 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Aicardi-Goutieres syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-1.0
CADD	Benign	1.1
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs114791229; hg19: chr20-35521047;