20-3230258-G-C

Position:

• chr20-3230258-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001174089.2(SLC4A11):​c.1418C>G​(p.Ser473Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S473L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC4A11 NM_001174089.2 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.74

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 topological_domain Cytoplasmic (size 7) in uniprot entity S4A11_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001174089.2
• 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-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 20-3230258-G-C is Pathogenic according to our data. Variant chr20-3230258-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1711855.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A11	NM_001174089.2	c.1418C>G	p.Ser473Trp	missense_variant, splice_region_variant	13/20	ENST00000642402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A11	ENST00000642402.1	c.1418C>G	p.Ser473Trp	missense_variant, splice_region_variant	13/20		NM_001174089.2	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital hereditary endothelial dystrophy of cornea Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Prof. Brien Holden Eye Research Center, Hyderabad Eye Research Foundation, L V Prasad Eye Institute

Aug 07, 2022

Opaque cornea with reduced visual acuity, Autosomal recessive -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.3	D;D;.;.;.;.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;.;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.93
MutPred		0.78		Gain of helix (P = 0.0854);.;.;.;.;.;.;
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.98

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: rs121909388; hg19: chr20-3210904;