chrX-74421416-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_006517.5(SLC16A2):c.-222A>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 5 hem., cov: 11)

Exomes 𝑓: 0.00097 ( 2 hom. 127 hem. )

Consequence

SLC16A2
NM_006517.5 upstream_gene

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.916

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Allan-Herndon-Dudley syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

SLC16A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.076).

BP6

Variant X-74421416-A-T is Benign according to our data. Variant chrX-74421416-A-T is described in CliVar as Benign/Likely_benign. Clinvar id is 193346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00112 (66/59151) while in subpopulation NFE AF = 0.00168 (55/32831). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 11. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A2	NM_006517.5 link	c.-222A>T		upstream_gene_variant		ENST00000587091.6	NP_006508.2	P36021

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC16A2	ENST00000587091.6 link	c.-222A>T		upstream_gene_variant		1	NM_006517.5	ENSP00000465734.1		P36021

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

AN:

59125

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000276

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000437

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000482

Gnomad MID

AF:

0.00794

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.00401

GnomAD2 exomes

AF:

0.000661

AC:

AN:

89247

AF XY:

0.000690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000216

Gnomad ASJ exome

AF:

0.000218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00108

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.000713

GnomAD4 exome

AF:

0.000970

AC:

364

AN:

375439

Hom.:

Cov.:

AF XY:

0.000979

AC XY:

127

AN XY:

129769

show subpopulations

African (AFR)

AF:

0.000252

AC:

AN:

11913

American (AMR)

AF:

0.000269

AC:

AN:

26030

Ashkenazi Jewish (ASJ)

AF:

0.0000762

AC:

AN:

13123

East Asian (EAS)

AF:

0.00

AC:

AN:

22133

South Asian (SAS)

AF:

0.000174

AC:

AN:

34435

European-Finnish (FIN)

AF:

0.000911

AC:

AN:

28530

Middle Eastern (MID)

AF:

0.00217

AC:

AN:

1844

European-Non Finnish (NFE)

AF:

0.00129

AC:

279

AN:

215788

Other (OTH)

AF:

0.00176

AC:

AN:

21643

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00112

AC:

AN:

59151

Hom.:

Cov.:

AF XY:

0.000488

AC XY:

AN XY:

10243

show subpopulations

African (AFR)

AF:

0.000276

AC:

AN:

14481

American (AMR)

AF:

0.000436

AC:

AN:

4586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1637

East Asian (EAS)

AF:

0.00

AC:

AN:

1579

South Asian (SAS)

AF:

0.00

AC:

AN:

700

European-Finnish (FIN)

AF:

0.000482

AC:

AN:

2073

Middle Eastern (MID)

AF:

0.00862

AC:

AN:

116

European-Non Finnish (NFE)

AF:

0.00168

AC:

AN:

32831

Other (OTH)

AF:

0.00398

AC:

AN:

754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000317

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 09, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 09, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 20, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.92

PromoterAI

-0.0091

Neutral

(source)

Mutation Taster

=164/36

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over