2-219629227-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_005070.4(SLC4A3):c.301A>C(p.Thr101Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SLC4A3 NM_005070.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.347

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC4A3
• BP4: Computational evidence support a benign effect (MetaRNN=0.08647278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A3	NM_005070.4	c.301A>C	p.Thr101Pro	missense_variant	4/23	ENST00000358055.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A3	ENST00000358055.8	c.301A>C	p.Thr101Pro	missense_variant	4/23	1	NM_005070.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245842 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134022

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460686 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.301A>C (p.T101P) alteration is located in exon 4 (coding exon 3) of the SLC4A3 gene. This alteration results from a A to C substitution at nucleotide position 301, causing the threonine (T) at amino acid position 101 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.44	N
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.086	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N
MutationTaster	Benign	0.95	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.90	N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.40	B;B;P;B
Vest4		0.26
MutPred		0.20		Loss of phosphorylation at T101 (P = 0.0125);Loss of phosphorylation at T101 (P = 0.0125);Loss of phosphorylation at T101 (P = 0.0125);Loss of phosphorylation at T101 (P = 0.0125);
MVP		0.42
ClinPred		0.081	T
GERP RS		2.6
Varity_R		0.13
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs766023665; hg19: chr2-220493949;