rs121909388

Variant names:

• chr20-3230258-G-A
• rs121909388
• NM_001174089.2:c.1418C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-3230258-G-A
• chr20-3230258-G-C
• chr20-3230258-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001174089.2(SLC4A11):​c.1418C>T​(p.Ser473Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S473W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC4A11 NM_001174089.2 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.74
• Publications: 21 publications found

Genes affected

SLC4A11 (HGNC:16438): (solute carrier family 4 member 11) This gene encodes a voltage-regulated, electrogenic sodium-coupled borate cotransporter that is essential for borate homeostasis, cell growth and cell proliferation. Mutations in this gene have been associated with a number of endothelial corneal dystrophies including recessive corneal endothelial dystrophy 2, corneal dystrophy and perceptive deafness, and Fuchs endothelial corneal dystrophy. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

SLC4A11 Gene-Disease associations (from GenCC):

• corneal dystrophy, Fuchs endothelial, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• congenital hereditary endothelial dystrophy of cornea

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• corneal dystrophy-perceptive deafness syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-3230258-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1711855.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 20-3230258-G-A is Pathogenic according to our data. Variant chr20-3230258-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174089.2. 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
	SLC4A11	NM_001174089.2	MANE Select	c.1418C>T	p.Ser473Leu	missense splice_region	Exon 13 of 20	NP_001167560.1	Q8NBS3-3
	SLC4A11	NM_001174090.2		c.1547C>T	p.Ser516Leu	missense splice_region	Exon 13 of 20	NP_001167561.1	Q8NBS3-4
	SLC4A11	NM_032034.4		c.1466C>T	p.Ser489Leu	missense splice_region	Exon 12 of 19	NP_114423.1	Q8NBS3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A11	ENST00000642402.1	MANE Select	c.1418C>T	p.Ser473Leu	missense splice_region	Exon 13 of 20	ENSP00000493503.1	Q8NBS3-3
	SLC4A11	ENST00000380056.7	TSL:1	c.1466C>T	p.Ser489Leu	missense splice_region	Exon 12 of 19	ENSP00000369396.3	Q8NBS3-1
	SLC4A11	ENST00000380059.7	TSL:2	c.1547C>T	p.Ser516Leu	missense splice_region	Exon 13 of 20	ENSP00000369399.3	Q8NBS3-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251098 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461140 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726874

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000104 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Congenital hereditary endothelial dystrophy of cornea (1)
1	-	-	Corneal dystrophy-perceptive deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.96
MPC		0.93
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.55
gMVP		0.95
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs121909388; hg19: chr20-3210904; COSMIC: COSV66263505; COSMIC: COSV66263505;