20-3230258-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. 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
• 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: Likely_pathogenic. The variant received 8 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-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.
• 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 VariationId is 1711855.Status of the report is criteria_provided_single_submitter, 1 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>G	p.Ser473Trp	missense splice_region	Exon 13 of 20	NP_001167560.1	Q8NBS3-3
	SLC4A11	NM_001174090.2		c.1547C>G	p.Ser516Trp	missense splice_region	Exon 13 of 20	NP_001167561.1	Q8NBS3-4
	SLC4A11	NM_032034.4		c.1466C>G	p.Ser489Trp	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>G	p.Ser473Trp	missense splice_region	Exon 13 of 20	ENSP00000493503.1	Q8NBS3-3
	SLC4A11	ENST00000380056.7	TSL:1	c.1466C>G	p.Ser489Trp	missense splice_region	Exon 12 of 19	ENSP00000369396.3	Q8NBS3-1
	SLC4A11	ENST00000380059.7	TSL:2	c.1547C>G	p.Ser516Trp	missense splice_region	Exon 13 of 20	ENSP00000369399.3	Q8NBS3-4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital hereditary endothelial dystrophy of cornea (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	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
Mutation Taster		=15/85	disease causing

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: rs121909388; hg19: chr20-3210904;