chr20-36892861-G-T

Position:

• chr20-36892861-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The NM_080628.3(TLDC2):​c.*18-1G>T variant causes a splice acceptor 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (45 hom.)
• Consequence: TLDC2 NM_080628.3 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.640

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 2.118827 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of 36, new splice context is: cctctaaatgaattgtgcAGgag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLDC2	NM_080628.3	c.*18-1G>T		splice_acceptor_variant		ENST00000217320.8
SAMHD1	NM_015474.4	c.*71C>A		3_prime_UTR_variant	16/16	ENST00000646673.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLDC2	ENST00000217320.8	c.*18-1G>T		splice_acceptor_variant		1	NM_080628.3	P1
SAMHD1	ENST00000646673.2	c.*71C>A		3_prime_UTR_variant	16/16		NM_015474.4	P1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152148 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00462 AC: 1151 AN: 248944 Hom.: 8 AF XY: 0.00569 AC XY: 767 AN XY: 134762

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 SAS exome AF: 0.0200

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.: 45 Cov.: 26 AF XY: 0.00536 AC XY: 3827 AN XY: 714356

Gnomad4 AFR exome AF: 0.000731

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00289

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0215

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00422

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00292 AC: 445 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74446

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00350 Hom.: 0

Bravo AF: 0.00261

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00545 AC: 21

ExAC AF: 0.00437 AC: 531

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00504

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 19, 2020

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.79
Eigen	Uncertain	0.32
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.22	N
MutationTaster	Benign	1.0	N;N
GERP RS		3.6

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

LitVar

Other links and lift over

dbSNP: rs138927042; hg19: chr20-35521264;