8-22624311-C-T

Variant names:

• chr8-22624311-C-T
• rs377437801
• NM_018688.6:c.391G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018688.6(BIN3):​c.391G>A​(p.Ala131Thr) 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 1,461,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A131P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BIN3 NM_018688.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

Genes affected

BIN3 (HGNC:1054): (bridging integrator 3) The product of this gene is a member of the BAR domain protein family. The encoded protein is comprised solely of a BAR domain which is predicted to form coiled-coil structures and proposed to mediate dimerization, sense and induce membrane curvature, and bind small GTPases. BAR domain proteins have been implicated in endocytosis, intracellular transport, and a diverse set of other processes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24318153).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018688.6. 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
	BIN3	NM_018688.6	MANE Select	c.391G>A	p.Ala131Thr	missense	Exon 7 of 9	NP_061158.1	Q9NQY0-1
	BIN3	NM_001363046.2		c.247G>A	p.Ala83Thr	missense	Exon 6 of 8	NP_001349975.1	H7BYV6
	BIN3	NR_156436.2		n.461G>A		non_coding_transcript_exon	Exon 7 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN3	ENST00000276416.11	TSL:1 MANE Select	c.391G>A	p.Ala131Thr	missense	Exon 7 of 9	ENSP00000276416.6	Q9NQY0-1
	BIN3	ENST00000853250.1		c.403G>A	p.Ala135Thr	missense	Exon 7 of 9	ENSP00000523309.1
	BIN3	ENST00000939253.1		c.328G>A	p.Ala110Thr	missense	Exon 7 of 9	ENSP00000609312.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461480 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727030

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.040
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.21
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.44		Gain of phosphorylation at A131 (P = 0.0124)
MVP		0.55
ClinPred		0.76	D
GERP RS		5.4
Varity_R		0.17
gMVP		0.19
Mutation Taster		=50/50

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: rs377437801; hg19: chr8-22481824;