X-154488397-C-T

Variant names:

• chrX-154488397-C-T
• rs138863812
• NM_019848.5:c.544G>A

Variant summary

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

The NM_019848.5(SLC10A3):​c.544G>A​(p.Ala182Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,209,719 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 256 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., 9 hem., cov: 24)
  • Exomes 𝑓: 0.00067 (0 hom. 247 hem.)
• Consequence: SLC10A3 NM_019848.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.67

Genes affected

SLC10A3 (HGNC:22979): (solute carrier family 10 member 3) This gene maps to a GC-rich region of the X chromosome and was identified by its proximity to a CpG island. It is thought to be a housekeeping gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015341133).
• BP6: Variant X-154488397-C-T is Benign according to our data. Variant chrX-154488397-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2352689.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154488397-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC10A3	NM_019848.5	c.544G>A	p.Ala182Thr	missense_variant	Exon 2 of 2	ENST00000651600.1	NP_062822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC10A3	ENST00000651600.1	c.544G>A	p.Ala182Thr	missense_variant	Exon 2 of 2		NM_019848.5	ENSP00000499188.1

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 37 AN: 112078 Hom.: 0 Cov.: 24 AF XY: 0.000263 AC XY: 9 AN XY: 34236

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000470

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000835

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000490

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000464 AC: 85 AN: 183143 Hom.: 0 AF XY: 0.000517 AC XY: 35 AN XY: 67747

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000649

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000671 AC: 737 AN: 1097587 Hom.: 0 Cov.: 31 AF XY: 0.000680 AC XY: 247 AN XY: 363149

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000265

Gnomad4 SAS exome AF: 0.0000924

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000798

Gnomad4 OTH exome AF: 0.000651

GnomAD4 genome AF: 0.000330 AC: 37 AN: 112132 Hom.: 0 Cov.: 24 AF XY: 0.000262 AC XY: 9 AN XY: 34300

Gnomad4 AFR AF: 0.0000969

Gnomad4 AMR AF: 0.000469

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000838

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000490

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000513 Hom.: 14

Bravo AF: 0.000314

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 21, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.0010
DANN	Benign	0.79
DEOGEN2	Benign	0.049	.;T;.;T;.
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.54	T;T;T;.;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.22	.;N;.;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.050	N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.73	T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.0010	.;B;.;B;.
Vest4		0.014
MVP		0.13
MPC		0.46
ClinPred		0.0020	T
GERP RS		-11
Varity_R		0.032
gMVP		0.24

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: rs138863812; hg19: chrX-153716736;