13-113495865-C-T

Variant names:

• chr13-113495865-C-T
• rs146463273
• NM_017905.6:c.284C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017905.6(SLC9D1):​c.284C>T​(p.Thr95Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC9D1 NM_017905.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.73
• Publications: 0 publications found

Genes affected

SLC9D1 (HGNC:20329): (transmembrane and coiled-coil domains 3) This gene encodes a member of the monovalent cation:proton antiporter 2 (CPA2) family of transporter proteins. Members of this family typically couple the export of monovalent cations, such as potassium or sodium, to the import of protons across cellular membranes. Mutations in this gene have been identified in patients with a rare inherited vision defect, cornea guttata with anterior polar cataract. [provided by RefSeq, Mar 2017]

SLC9D1 Gene-Disease associations (from GenCC):

• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19981349).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017905.6. 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
	SLC9D1	NM_017905.6	MANE Select	c.284C>T	p.Thr95Met	missense	Exon 2 of 13	NP_060375.4
	SLC9D1	NM_001349744.2		c.284C>T	p.Thr95Met	missense	Exon 2 of 12	NP_001336673.1
	SLC9D1	NM_001349742.2		c.284C>T	p.Thr95Met	missense	Exon 2 of 12	NP_001336671.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO3	ENST00000434316.7	TSL:1 MANE Select	c.284C>T	p.Thr95Met	missense	Exon 2 of 13	ENSP00000389399.2	Q6UWJ1-1
	TMCO3	ENST00000375391.5	TSL:1	c.284C>T	p.Thr95Met	missense	Exon 2 of 8	ENSP00000364540.1	Q6UWJ1-3
	TMCO3	ENST00000955127.1		c.284C>T	p.Thr95Met	missense	Exon 2 of 14	ENSP00000625186.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251418 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.043
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.041	D
Sift4G	Uncertain	0.015	D
Polyphen		0.20	B
Vest4		0.34
MVP		0.061
MPC		0.28
ClinPred		0.14	T
GERP RS		3.7
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.57
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146463273; hg19: chr13-114150180;