Variant 17-68992208-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080283.4(ABCA9):c.3683G>A(p.Arg1228Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,448,866 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: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ABCA9
NM_080283.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07

Variant links:

Genes affected

ABCA9 (HGNC:39): (ATP binding cassette subfamily A member 9) This gene is a member of the superfamily of ATP-binding cassette (ABC) transporters and the encoded protein contains two transmembrane domains and two nucleotide binding folds. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This gene is a member of the ABC1 subfamily and is clustered with four other ABC1 family members on chromosome 17q24. Transcriptional expression of this gene is induced during monocyte differentiation into macrophages and is suppressed by cholesterol import. [provided by RefSeq, Jul 2008]

ABCA9 links:

ABCA9-AS1 (HGNC:39983): (ABCA9 antisense RNA 1)

ABCA9-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA9	NM_080283.4 linkuse as main transcript	c.3683G>A	p.Arg1228Lys	missense_variant	28/39	ENST00000340001.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA9	ENST00000340001.9 linkuse as main transcript	c.3683G>A	p.Arg1228Lys	missense_variant	28/39	1	NM_080283.4	P1	Q8IUA7-1
ABCA9-AS1	ENST00000630625.1 linkuse as main transcript	n.378-19775C>T		intron_variant, non_coding_transcript_variant		5
ABCA9	ENST00000453985.6 linkuse as main transcript	c.3569G>A	p.Arg1190Lys	missense_variant	27/38	5
ABCA9	ENST00000460872.1 linkuse as main transcript	n.475G>A		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000414

AC:

AN:

241702

Hom.:

AF XY:

0.00000767

AC XY:

AN XY:

130354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000908

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1448866

Hom.:

Cov.:

AF XY:

0.00000973

AC XY:

AN XY:

719576

show subpopulations

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:

0.0000145

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.3683G>A (p.R1228K) alteration is located in exon 28 (coding exon 27) of the ABCA9 gene. This alteration results from a G to A substitution at nucleotide position 3683, causing the arginine (R) at amino acid position 1228 to be replaced by a lysine (K). 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

0.094

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.067

T;.

Eigen

Benign

-0.017

Eigen_PC

Benign

0.0021

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.33

T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

0.63

D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.68

N;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.010

D;.

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.35

B;.

Vest4

0.27

MutPred

0.56

Gain of methylation at R1228 (P = 0.0075);.;

MVP

0.89

MPC

0.13

ClinPred

0.58

GERP RS

5.3

Varity_R

0.21

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 12

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over