X-74421523-A-AGGCAGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006517.5(SLC16A2):c.-102_-97dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 984,326 control chromosomes in the GnomAD database, including 46 homozygotes. There are 478 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., 260 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (22 hom. 218 hem.)
• Consequence: SLC16A2 NM_006517.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.19

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 -16 ACMG points.

• BP6: Variant X-74421523-A-AGGCAGC is Benign according to our data. Variant chrX-74421523-A-AGGCAGC is described in ClinVar as [Likely_benign]. Clinvar id is 587847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1167/111225) while in subpopulation AFR AF= 0.0364 (1111/30521). AF 95% confidence interval is 0.0346. There are 24 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A2	NM_006517.5	c.-102_-97dup		5_prime_UTR_variant	1/6	ENST00000587091.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A2	ENST00000587091.6	c.-102_-97dup		5_prime_UTR_variant	1/6	1	NM_006517.5	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1163 AN: 111179 Hom.: 24 Cov.: 22 AF XY: 0.00774 AC XY: 259 AN XY: 33451

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00404

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000568

Gnomad OTH AF: 0.00602

GnomAD3 exomes AF: 0.00249 AC: 296 AN: 118869 Hom.: 5 AF XY: 0.00147 AC XY: 56 AN XY: 38041

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.000786

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000679

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00117 AC: 1020 AN: 873101 Hom.: 22 Cov.: 16 AF XY: 0.000894 AC XY: 218 AN XY: 243865

Gnomad4 AFR exome AF: 0.0389

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000275

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.0105 AC: 1167 AN: 111225 Hom.: 24 Cov.: 22 AF XY: 0.00776 AC XY: 260 AN XY: 33507

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.00403

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000568

Gnomad4 OTH AF: 0.00594

Asia WGS AF: 0.00120 AC: 3 AN: 2520

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2019

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2020

- -

Allan-Herndon-Dudley syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs760787234; hg19: chrX-73641358;