Genetic Variant ARB2A:p.Lys387Gln (chr5-93621079-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_032042.6(ARB2A):c.1159A>C(p.Lys387Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,611,854 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 (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ARB2A
NM_032042.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95

Variant links:

Genes affected

ARB2A (HGNC:25365): (ARB2 cotranscriptional regulator A) Predicted to contribute to siRNA binding activity. Predicted to be involved in heterochromatin assembly by small RNA; neural crest cell development; and regulation of alternative mRNA splicing, via spliceosome. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ARB2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3791985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARB2A	NM_032042.6 link	c.1159A>C	p.Lys387Gln	missense_variant	Exon 11 of 11	ENST00000395965.8	NP_114431.2	Q8WUF8-1A0A024RAL9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARB2A	ENST00000395965.8 link	c.1159A>C	p.Lys387Gln	missense_variant	Exon 11 of 11	1	NM_032042.6	ENSP00000379294.3		Q8WUF8-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726164

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33326

American (AMR)

AF:

0.00

AC:

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39462

South Asian (SAS)

AF:

0.00

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111044

Other (OTH)

AF:

0.00

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1159A>C (p.K387Q) alteration is located in exon 11 (coding exon 10) of the FAM172A gene. This alteration results from a A to C substitution at nucleotide position 1159, causing the lysine (K) at amino acid position 387 to be replaced by a glutamine (Q). 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

0.10

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

T;.;.;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

T;T;T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.38

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.1

M;.;.;.

PhyloP100

4.9

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.045

D;D;D;T

Sift4G

Benign

0.068

T;T;D;T

Polyphen

0.95

P;.;D;.

Vest4

0.34

MutPred

0.49

Loss of methylation at K387 (P = 2e-04);.;.;.;

MVP

0.46

MPC

1.1

ClinPred

0.85

GERP RS

2.1

Varity_R

0.36

gMVP

0.49

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr5-93621079-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over