2-219629297-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005070.4(SLC4A3):c.371C>T(p.Pro124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,496 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC4A3 NM_005070.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.83

Genes affected

SLC4A3 (HGNC:11029): (solute carrier family 4 member 3) The protein encoded by this gene is a plasma membrane anion exchange protein. The encoded protein has been found in brain, heart, kidney, small intestine, and lung. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC4A3
• BP4: Computational evidence support a benign effect (MetaRNN=0.34424436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A3	NM_005070.4	c.371C>T	p.Pro124Leu	missense_variant	4/23	ENST00000358055.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A3	ENST00000358055.8	c.371C>T	p.Pro124Leu	missense_variant	4/23	1	NM_005070.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727028

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Martin Pollak Laboratory, Beth Israel Deaconess Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Benign	0.066	T;T;T;T
Polyphen		0.98	D;D;D;D
Vest4		0.47
MutPred		0.29		Loss of glycosylation at P124 (P = 0.0485);Loss of glycosylation at P124 (P = 0.0485);Loss of glycosylation at P124 (P = 0.0485);Loss of glycosylation at P124 (P = 0.0485);
MVP		0.58
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.14
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs387907531; hg19: chr2-220494019; COSMIC: COSV99813346; COSMIC: COSV99813346;