chrX-74421585-A-C

Variant names:

• chrX-74421585-A-C
• rs587784385
• NM_006517.5:c.-53A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006517.5(SLC16A2):​c.-53A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000039 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC16A2 NM_006517.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.537
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.07).

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.-53A>C		5_prime_UTR	Exon 1 of 6	NP_006508.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	ENST00000587091.6	TSL:1 MANE Select	c.-53A>C		5_prime_UTR	Exon 1 of 6	ENSP00000465734.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111814 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000637 AC: 89 AN: 139645 AF XY: 0.00

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.000148

Gnomad EAS exome AF: 0.000978

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000394 AC: 42 AN: 1067260 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 342082

African (AFR) AF: 0.00 AC: 0 AN: 25898

American (AMR) AF: 0.0000303 AC: 1 AN: 32986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19026

East Asian (EAS) AF: 0.00 AC: 0 AN: 29321

South Asian (SAS) AF: 0.00 AC: 0 AN: 51995

European-Finnish (FIN) AF: 0.000948 AC: 33 AN: 34817

Middle Eastern (MID) AF: 0.000928 AC: 3 AN: 3234

European-Non Finnish (NFE) AF: 0.00000364 AC: 3 AN: 824948

Other (OTH) AF: 0.0000444 AC: 2 AN: 45035

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000894 AC: 1 AN: 111814 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30812

American (AMR) AF: 0.00 AC: 0 AN: 10700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3518

South Asian (SAS) AF: 0.00 AC: 0 AN: 2671

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52879

Other (OTH) AF: 0.00 AC: 0 AN: 1506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Allan-Herndon-Dudley syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.93
PhyloP100		0.54
PromoterAI		0.10	Neutral

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: rs587784385; hg19: chrX-73641420; COSMIC: COSV52083584; COSMIC: COSV52083584;