rs759933264

Positions:

chrX-74521097-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006517.5(SLC16A2):c.538G>A(p.Val180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,210,501 control chromosomes in the GnomAD database, including 2 homozygotes. There are 64 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., 23 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 1 hom. 41 hem. )

Consequence

SLC16A2
NM_006517.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.489

Variant links:

Genes affected

SLC16A2 (HGNC:10923): (solute carrier family 16 member 2) This gene encodes an integral membrane protein that functions as a transporter of thyroid hormone. The encoded protein facilitates the cellular importation of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and diidothyronine (T2). This gene is expressed in many tissues and likely plays an important role in the development of the central nervous system. Loss of function mutations in this gene are associated with psychomotor retardation in males while females exhibit no neurological defects and more moderate thyroid-deficient phenotypes. This gene is subject to X-chromosome inactivation. Mutations in this gene are the cause of Allan-Herndon-Dudley syndrome. [provided by RefSeq, Mar 2012]

SLC16A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010031223).

BP6

Variant X-74521097-G-A is Benign according to our data. Variant chrX-74521097-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74521097-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000481 (54/112341) while in subpopulation AMR AF= 0.00432 (46/10636). AF 95% confidence interval is 0.00333. There are 1 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC16A2	NM_006517.5 link	c.538G>A	p.Val180Ile	missense_variant	2/6	ENST00000587091.6	NP_006508.2	P36021

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC16A2	ENST00000587091.6 link	c.538G>A	p.Val180Ile	missense_variant	2/6	1	NM_006517.5	ENSP00000465734.1	P36021
SLC16A2	ENST00000636771.1 link	n.*239G>A		non_coding_transcript_exon_variant	3/7	5		ENSP00000490445.1	A0A1B0GVB4
SLC16A2	ENST00000636771.1 link	n.*239G>A		3_prime_UTR_variant	3/7	5		ENSP00000490445.1	A0A1B0GVB4
SLC16A2	ENST00000590447.1 link	c.-24G>A		upstream_gene_variant		5		ENSP00000466213.1	K7ELT4

Frequencies

GnomAD3 genomes

AF:

0.000481

AC:

AN:

112289

Hom.:

Cov.:

AF XY:

0.000668

AC XY:

AN XY:

34441

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.000369

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00133

GnomAD3 exomes

AF:

0.000327

AC:

AN:

183483

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

67919

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.000114

AC:

125

AN:

1098160

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

363514

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000481

AC:

AN:

112341

Hom.:

Cov.:

AF XY:

0.000667

AC XY:

AN XY:

34503

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00432

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.000370

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000688

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2018

This alteration is classified as 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.6

DANN

Benign

0.93

DEOGEN2

Benign

0.18

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.83

M_CAP

Benign

0.0067

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.035

PrimateAI

Benign

0.33

Sift4G

Benign

0.75

Polyphen

0.032

Vest4

0.068

MutPred

0.55

Loss of catalytic residue at V180 (P = 0.2057);

MVP

0.068

MPC

0.72

ClinPred

0.0081

GERP RS

0.90

Varity_R

0.041

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over