rs367543059

chrX-74529295-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_006517.5(SLC16A2):c.1253T>C(p.Leu418Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_006517.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant X-74529295-T-C is Pathogenic according to our data. Variant chrX-74529295-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42110.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A2	NM_006517.5	c.1253T>C	p.Leu418Pro	missense_variant	5/6	ENST00000587091.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A2	ENST00000587091.6	c.1253T>C	p.Leu418Pro	missense_variant	5/6	1	NM_006517.5	P1
SLC16A2	ENST00000590447.1	c.611-2038T>C		intron_variant		5
SLC16A2	ENST00000636771.1	c.*954T>C		3_prime_UTR_variant, NMD_transcript_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics laboratory, Necker Hospital

Apr 16, 2020

- -

Allan-Herndon-Dudley syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.57		Loss of stability (P = 0.0029);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.96

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: rs367543059; hg19: chrX-73749130;