4-101830146-A-T

Variant summary

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

The NM_017935.5(BANK1):c.409A>T(p.Ile137Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I137V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BANK1 NM_017935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

BANK1 (HGNC:18233): (B cell scaffold protein with ankyrin repeats 1) The protein encoded by this gene is a B-cell-specific scaffold protein that functions in B-cell receptor-induced calcium mobilization from intracellular stores. This protein can also promote Lyn-mediated tyrosine phosphorylation of inositol 1,4,5-trisphosphate receptors. Polymorphisms in this gene are associated with susceptibility to systemic lupus erythematosus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29251045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BANK1	NM_017935.5	c.409A>T	p.Ile137Phe	missense_variant	2/17	ENST00000322953.9
BANK1	NM_001083907.3	c.319A>T	p.Ile107Phe	missense_variant	2/17
BANK1	NM_001127507.3	c.71-24889A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BANK1	ENST00000322953.9	c.409A>T	p.Ile137Phe	missense_variant	2/17	1	NM_017935.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.409A>T (p.I137F) alteration is located in exon 2 (coding exon 2) of the BANK1 gene. This alteration results from a A to T substitution at nucleotide position 409, causing the isoleucine (I) at amino acid position 137 to be replaced by a phenylalanine (F). 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	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	0.11
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.65	D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.92	P;P;.
Vest4		0.49
MutPred		0.56		.;Loss of sheet (P = 0.1158);.;
MVP		0.32
MPC		0.079
ClinPred		0.77	D
GERP RS		2.6
Varity_R		0.18
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-102751303;