NM_006517.5:c.1399+43T>G

Variant names:

• chrX-74529484-T-G
• rs5937843
• NM_006517.5:c.1399+43T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006517.5(SLC16A2):​c.1399+43T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 110,541 control chromosomes in the GnomAD database, including 16,119 homozygotes. There are 18,552 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (16119 hom., 18552 hem., cov: 22)
  • Exomes 𝑓: 0.75 (199128 hom. 204718 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC16A2 NM_006517.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0840
• Publications: 12 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-74529484-T-G is Benign according to our data. Variant chrX-74529484-T-G is described in ClinVar as Benign. ClinVar VariationId is 159903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006517.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	NM_006517.5	MANE Select	c.1399+43T>G		intron	N/A	NP_006508.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	ENST00000587091.6	TSL:1 MANE Select	c.1399+43T>G		intron	N/A	ENSP00000465734.1
	SLC16A2	ENST00000590447.1	TSL:5	c.610-1849T>G		intron	N/A	ENSP00000466213.1
	SLC16A2	ENST00000636771.1	TSL:5	n.*1100+43T>G		intron	N/A	ENSP00000490445.1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 63643 AN: 110491 Hom.: 16133 Cov.: 22

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.873

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.0334

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.720

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.610

GnomAD2 exomes AF: 0.606 AC: 63477 AN: 104815 AF XY: 0.616

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.475

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 0.0318

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.810

Gnomad OTH exome AF: 0.687

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.754 AC: 705707 AN: 935708 Hom.: 199128 Cov.: 16 AF XY: 0.760 AC XY: 204718 AN XY: 269428

African (AFR) AF: 0.212 AC: 4658 AN: 21951

American (AMR) AF: 0.478 AC: 13032 AN: 27249

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 13860 AN: 17755

East Asian (EAS) AF: 0.0208 AC: 548 AN: 26388

South Asian (SAS) AF: 0.503 AC: 23412 AN: 46517

European-Finnish (FIN) AF: 0.775 AC: 26028 AN: 33598

Middle Eastern (MID) AF: 0.770 AC: 2201 AN: 2857

European-Non Finnish (NFE) AF: 0.826 AC: 593737 AN: 718952

Other (OTH) AF: 0.698 AC: 28231 AN: 40441

GnomAD4 genome AF: 0.576 AC: 63643 AN: 110541 Hom.: 16119 Cov.: 22 AF XY: 0.565 AC XY: 18552 AN XY: 32807

African (AFR) AF: 0.211 AC: 6452 AN: 30515

American (AMR) AF: 0.514 AC: 5342 AN: 10385

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2040 AN: 2618

East Asian (EAS) AF: 0.0332 AC: 117 AN: 3521

South Asian (SAS) AF: 0.449 AC: 1181 AN: 2630

European-Finnish (FIN) AF: 0.776 AC: 4471 AN: 5764

Middle Eastern (MID) AF: 0.721 AC: 155 AN: 215

European-Non Finnish (NFE) AF: 0.804 AC: 42393 AN: 52716

Other (OTH) AF: 0.601 AC: 901 AN: 1500

Alfa AF: 0.711 Hom.: 70921

Bravo AF: 0.541

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allan-Herndon-Dudley syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.58
DANN	Benign	0.55
PhyloP100		0.084
Mutation Taster		=5/95	disease causing

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

Other links and lift over

dbSNP: rs5937843; hg19: chrX-73749319; COSMIC: COSV52084469;