ENST00000464157.1:n.421T>C

Variant names:

• chr9-137008260-A-G
• rs4880185
• ENST00000464157.1:n.421T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000464157.1(ABCA2):​n.421T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 913,584 control chromosomes in the GnomAD database, including 427,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70799 hom., cov: 32)
  • Exomes 𝑓: 0.97 (356826 hom.)
• Consequence: ABCA2 ENST00000464157.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.286
• Publications: 5 publications found

Genes affected

ABCA2 (HGNC:32): (ATP binding cassette subfamily A member 2) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. 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, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is highly expressed in brain tissue and may play a role in macrophage lipid metabolism and neural development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ABCA2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with poor growth and with or without seizures or ataxia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-137008260-A-G is Benign according to our data. Variant chr9-137008260-A-G is described in ClinVar as [Benign]. Clinvar id is 1185556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5	c.7275+156T>C		intron_variant	Intron 48 of 48	ENST00000341511.11	NP_001597.2
ABCA2	NM_212533.3	c.7365+156T>C		intron_variant	Intron 48 of 48		NP_997698.1
ABCA2	NM_001411042.1	c.7272+156T>C		intron_variant	Intron 47 of 47		NP_001397971.1
ABCA2	XM_047422921.1	c.7362+156T>C		intron_variant	Intron 47 of 47		XP_047278877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11	c.7275+156T>C		intron_variant	Intron 48 of 48	5	NM_001606.5	ENSP00000344155.6

Frequencies

GnomAD3 genomes AF: 0.964 AC: 146730 AN: 152162 Hom.: 70749 Cov.: 32

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.972

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.986

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.961

GnomAD2 exomes AF: 0.974 AC: 127432 AN: 130874 AF XY: 0.974

Gnomad AFR exome AF: 0.955

Gnomad AMR exome AF: 0.983

Gnomad ASJ exome AF: 0.963

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.969

Gnomad NFE exome AF: 0.964

Gnomad OTH exome AF: 0.973

GnomAD4 exome AF: 0.968 AC: 737033 AN: 761304 Hom.: 356826 Cov.: 10 AF XY: 0.968 AC XY: 385436 AN XY: 398034

African (AFR) AF: 0.955 AC: 18810 AN: 19688

American (AMR) AF: 0.982 AC: 34244 AN: 34878

Ashkenazi Jewish (ASJ) AF: 0.962 AC: 20445 AN: 21252

East Asian (EAS) AF: 1.00 AC: 32942 AN: 32944

South Asian (SAS) AF: 0.984 AC: 65096 AN: 66158

European-Finnish (FIN) AF: 0.971 AC: 32669 AN: 33648

Middle Eastern (MID) AF: 0.979 AC: 4426 AN: 4520

European-Non Finnish (NFE) AF: 0.964 AC: 492220 AN: 510778

Other (OTH) AF: 0.966 AC: 36181 AN: 37438

GnomAD4 genome AF: 0.964 AC: 146838 AN: 152280 Hom.: 70799 Cov.: 32 AF XY: 0.966 AC XY: 71891 AN XY: 74442

African (AFR) AF: 0.956 AC: 39738 AN: 41566

American (AMR) AF: 0.972 AC: 14883 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 3326 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5174

South Asian (SAS) AF: 0.986 AC: 4753 AN: 4822

European-Finnish (FIN) AF: 0.966 AC: 10257 AN: 10622

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.963 AC: 65491 AN: 68004

Other (OTH) AF: 0.962 AC: 2033 AN: 2114

Alfa AF: 0.963 Hom.: 16645

Bravo AF: 0.964

Asia WGS AF: 0.991 AC: 3447 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with poor growth and with or without seizures or ataxia Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.9
DANN	Benign	0.66
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs4880185; hg19: chr9-139902712; COSMIC: COSV55803117; COSMIC: COSV55803117;