rs759933264

chrX-74521097-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006517.5(SLC16A2):c.538G>A(p.Val180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,210,501 control chromosomes in the GnomAD database, including 2 homozygotes. There are 64 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V180F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., 23 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (1 hom. 41 hem.)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.489

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010031223).
• BP6: Variant X-74521097-G-A is Benign according to our data. Variant chrX-74521097-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74521097-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000481 (54/112341) while in subpopulation AMR AF= 0.00432 (46/10636). AF 95% confidence interval is 0.00333. There are 1 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A2	NM_006517.5	c.538G>A	p.Val180Ile	missense_variant	2/6	ENST00000587091.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A2	ENST00000587091.6	c.538G>A	p.Val180Ile	missense_variant	2/6	1	NM_006517.5	P1
SLC16A2	ENST00000636771.1	c.*239G>A		3_prime_UTR_variant, NMD_transcript_variant	3/7	5
SLC16A2	ENST00000590447.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000481 AC: 54 AN: 112289 Hom.: 1 Cov.: 23 AF XY: 0.000668 AC XY: 23 AN XY: 34441

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000327 AC: 60 AN: 183483 Hom.: 1 AF XY: 0.000280 AC XY: 19 AN XY: 67919

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.000882

GnomAD4 exome AF: 0.000114 AC: 125 AN: 1098160 Hom.: 1 Cov.: 31 AF XY: 0.000113 AC XY: 41 AN XY: 363514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000481 AC: 54 AN: 112341 Hom.: 1 Cov.: 23 AF XY: 0.000667 AC XY: 23 AN XY: 34503

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000751

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000136 Hom.: 1

Bravo AF: 0.000688

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2018

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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	6.6
Dann	Benign	0.93
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.035	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.75	T
Polyphen		0.032	B
Vest4		0.068
MutPred		0.55		Loss of catalytic residue at V180 (P = 0.2057);
MVP		0.068
MPC		0.72
ClinPred		0.0081	T
GERP RS		0.90
Varity_R		0.041
gMVP		0.27

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: rs759933264; hg19: chrX-73740932;