rs1363308293

Variant names:

• chrX-74529432-C-A
• rs1363308293
• NM_006517.5:c.1390C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-74529432-C-A
• chrX-74529432-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_006517.5(SLC16A2):​c.1390C>A​(p.Pro464Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P464S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-74529432-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559939.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant X-74529432-C-A is Pathogenic according to our data. Variant chrX-74529432-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1805190.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A2	NM_006517.5	c.1390C>A	p.Pro464Thr	missense_variant	Exon 5 of 6	ENST00000587091.6	NP_006508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC16A2	ENST00000587091.6	c.1390C>A	p.Pro464Thr	missense_variant	Exon 5 of 6	1	NM_006517.5	ENSP00000465734.1
SLC16A2	ENST00000636771.1	n.*1091C>A		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000490445.1
SLC16A2	ENST00000636771.1	n.*1091C>A		3_prime_UTR_variant	Exon 6 of 7	5		ENSP00000490445.1
SLC16A2	ENST00000590447.1	c.610-1901C>A		intron_variant	Intron 3 of 3	5		ENSP00000466213.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Allan-Herndon-Dudley syndrome Pathogenic:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Allan-Herndon-Dudley syndrome (MIM#300523). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are known to be affected with the full range of symptoms associated with Allan-Herndon-Dudley syndrome while some heterozygous females develop a mild thyroid phenotype but no neurological symptoms (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to threonine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Another missense variant and inframe deletion comparable to the one identified in this case has moderate previous evidence for pathogenicity. These variants (p.(Pro464del)) and p.(Pro464Ser) have each been seen in one individual with Allan-Herndon-Dudley syndrome (PMID:27081503, 32277047). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0903 - This variant has limited evidence for segregation with disease. It has been found in two similarly affected hemizygous maternal great uncles. (SP) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function. This individual has been found to have increased free triiodothyronin (FT3). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.67		Gain of glycosylation at P464 (P = 0.0253);
MVP		0.98
MPC		2.1
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.95
Mutation Taster		=22/78	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: rs1363308293; hg19: chrX-73749267;