rs121909394

chr20-3228337-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PM1 PP3_Strong PP5_Very_Strong BS2

The NM_001174089.2(SLC4A11):c.2480T>C(p.Leu827Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,612,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L827L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: SLC4A11 NM_001174089.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.44

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical (size 16) in uniprot entity S4A11_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001174089.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 20-3228337-A-G is Pathogenic according to our data. Variant chr20-3228337-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-3228337-A-G is described in Lovd as [Pathogenic]. Variant chr20-3228337-A-G is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A11	NM_001174089.2	c.2480T>C	p.Leu827Pro	missense_variant	19/20	ENST00000642402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A11	ENST00000642402.1	c.2480T>C	p.Leu827Pro	missense_variant	19/20		NM_001174089.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152058 Hom.: 0 Cov.: 30

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251080 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1460886 Hom.: 0 Cov.: 36 AF XY: 0.0000454 AC XY: 33 AN XY: 726780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152058 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy-perceptive deafness syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2023	Variant summary: SLC4A11 c.2528T>C (p.Leu843Pro) results in a non-conservative amino acid change located in the transmembrane region 14 (TM14) (Badior_2016) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251080 control chromosomes (gnomAD). c.2528T>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Corneal Dystrophy And Perceptive Deafness (Desir_2007, Hand_2016). In addition, this variant was co-segregated with disease in one family (Hand_2016). These data indicate that the variant is very likely to be associated with disease. At least two functional studies reported this variant failed to reach the cell surface in transfected cells (Loganathan_2014, Alka_2018). Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 24, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 20, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC4A11 function (PMID: 24916015, 29327391). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC4A11 protein function. ClinVar contains an entry for this variant (Variation ID: 1316). This missense change has been observed in individual(s) with Harboyan syndrome (PMID: 17220209, 27057589). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909394, gnomAD 0.005%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 843 of the SLC4A11 protein (p.Leu843Pro). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -

Congenital hereditary endothelial dystrophy of cornea;C1857572:Corneal dystrophy-perceptive deafness syndrome;C2750450:Corneal dystrophy, Fuchs endothelial, 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;.;T;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.1	D;D;.;.;.;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;.;.;.;.;D
Polyphen		0.34	B;.;.;.;.;.;.
Vest4		0.93
MutPred		0.89		Gain of catalytic residue at L843 (P = 0.007);.;.;.;.;.;.;
MVP		0.94
MPC		0.86
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909394; hg19: chr20-3208983;