X-30560133-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_025159.3(TASL):c.223C>A(p.His75Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000482 in 1,208,818 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 187 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00048 (0 hom. 178 hem.)
• Consequence: TASL NM_025159.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.746

Genes affected

TASL (HGNC:25667): (TLR adaptor interacting with endolysosomal SLC15A4) Involved in positive regulation of innate immune response; positive regulation of toll-like receptor signaling pathway; and regulation of lysosomal lumen pH. Located in endolysosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012600362).
• BP6: Variant X-30560133-G-T is Benign according to our data. Variant chrX-30560133-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1328361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-30560133-G-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TASL	NM_025159.3	c.223C>A	p.His75Asn	missense_variant	3/3	ENST00000378962.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TASL	ENST00000378962.4	c.223C>A	p.His75Asn	missense_variant	3/3	1	NM_025159.3	P1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 53 AN: 112159 Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9 AN XY: 34317

Gnomad AFR AF: 0.0000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000920

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.000497 AC: 90 AN: 180981 Hom.: 0 AF XY: 0.000534 AC XY: 35 AN XY: 65581

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000190

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000483 AC: 530 AN: 1096659 Hom.: 0 Cov.: 32 AF XY: 0.000492 AC XY: 178 AN XY: 362099

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000854

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000597

Gnomad4 OTH exome AF: 0.000369

GnomAD4 genome AF: 0.000473 AC: 53 AN: 112159 Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9 AN XY: 34317

Gnomad4 AFR AF: 0.0000647

Gnomad4 AMR AF: 0.0000947

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000920

Gnomad4 OTH AF: 0.000662

Alfa AF: 0.000758 Hom.: 33

Bravo AF: 0.000348

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000634 AC: 77

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TASL: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	8.8
Dann	Benign	0.83
DEOGEN2	Benign	0.054	T
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.55	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.042
Sift	Benign	0.22	T
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.25
MPC		0.25
ClinPred		0.026	T
GERP RS		4.4
Varity_R		0.17
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs150122685; hg19: chrX-30578250;