rs1555989369

Positions:

• chrX-74521051-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006517.5(SLC16A2):​c.492C>A​(p.Phe164Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.86

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC16A2	NM_006517.5	c.492C>A	p.Phe164Leu	missense_variant	2/6	ENST00000587091.6	NP_006508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC16A2	ENST00000587091.6	c.492C>A	p.Phe164Leu	missense_variant	2/6	1	NM_006517.5	ENSP00000465734	P1
SLC16A2	ENST00000636771.1	c.*193C>A		3_prime_UTR_variant, NMD_transcript_variant	3/7	5		ENSP00000490445

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 26, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC16A2 protein function. ClinVar contains an entry for this variant (Variation ID: 521184). This variant has not been reported in the literature in individuals affected with SLC16A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 164 of the SLC16A2 protein (p.Phe164Leu). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.492C>A (p.F164L) alteration is located in exon 2 (coding exon 2) of the SLC16A2 gene. This alteration results from a C to A substitution at nucleotide position 492, causing the phenylalanine (F) at amino acid position 164 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.F164L amino acid is located in a domain that is a member of the Major Facilitator Superfamily a large and diverse group of secondary transporters that includes uniporters, symporters, and antiporters. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2021

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.38	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.84
MutPred		0.46		Loss of helix (P = 0.1299);
MVP		0.99
MPC		1.1
ClinPred		0.56	D
GERP RS		4.1
Varity_R		0.53
gMVP		0.77

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: rs1555989369; hg19: chrX-73740886;