chrX-74524656-A-T

Variant names:

• chrX-74524656-A-T
• rs12849161
• NM_006517.5:c.873A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006517.5(SLC16A2):​c.873A>T​(p.Pro291Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,209,790 control chromosomes in the GnomAD database, including 29 homozygotes. There are 562 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (16 hom., 264 hem., cov: 22)
  • Exomes 𝑓: 0.00097 (13 hom. 298 hem.)
• Consequence: SLC16A2 NM_006517.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.39
• Publications: 3 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: ClinGen, G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-74524656-A-T is Benign according to our data. Variant chrX-74524656-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0084 (937/111583) while in subpopulation AFR AF = 0.0289 (886/30667). AF 95% confidence interval is 0.0273. There are 16 homozygotes in GnomAd4. There are 264 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	NM_006517.5	MANE Select	c.873A>T	p.Pro291Pro	synonymous	Exon 3 of 6	NP_006508.2	P36021

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	ENST00000587091.6	TSL:1 MANE Select	c.873A>T	p.Pro291Pro	synonymous	Exon 3 of 6	ENSP00000465734.1	P36021
	SLC16A2	ENST00000878592.1		c.987A>T	p.Pro329Pro	synonymous	Exon 4 of 7	ENSP00000548651.1
	SLC16A2	ENST00000922847.1		c.951A>T	p.Pro317Pro	synonymous	Exon 4 of 7	ENSP00000592906.1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 936 AN: 111528 Hom.: 16 Cov.: 22

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00398

GnomAD2 exomes AF: 0.00250 AC: 459 AN: 183296 AF XY: 0.00183

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000965 AC: 1060 AN: 1098207 Hom.: 13 Cov.: 33 AF XY: 0.000820 AC XY: 298 AN XY: 363565

African (AFR) AF: 0.0327 AC: 864 AN: 26403

American (AMR) AF: 0.00176 AC: 62 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000923 AC: 5 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.000483 AC: 2 AN: 4137

European-Non Finnish (NFE) AF: 0.0000202 AC: 17 AN: 842115

Other (OTH) AF: 0.00239 AC: 110 AN: 46097

GnomAD4 genome AF: 0.00840 AC: 937 AN: 111583 Hom.: 16 Cov.: 22 AF XY: 0.00781 AC XY: 264 AN XY: 33797

African (AFR) AF: 0.0289 AC: 886 AN: 30667

American (AMR) AF: 0.00407 AC: 43 AN: 10559

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6042

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53090

Other (OTH) AF: 0.00393 AC: 6 AN: 1528

Alfa AF: 0.00423 Hom.: 19

Bravo AF: 0.0102

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spastic paraplegia (1)
-	-	-	Allan-Herndon-Dudley syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.8
DANN	Benign	0.73
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs12849161; hg19: chrX-73744491;