9-104826974-C-T

Variant names:

• chr9-104826974-C-T
• rs2066718
• NM_005502.4:c.2311G>A

Variant summary

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

The NM_005502.4(ABCA1):​c.2311G>A​(p.Val771Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,990 control chromosomes in the GnomAD database, including 1,908 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V771L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (346 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1562 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80
• Publications: 73 publications found

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) 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. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

ABCA1 Gene-Disease associations (from GenCC):

• hypoalphalipoproteinemia, primary, 1

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tangier disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017911494).
• BP6: Variant 9-104826974-C-T is Benign according to our data. Variant chr9-104826974-C-T is described in ClinVar as Benign. ClinVar VariationId is 364433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.2311G>A	p.Val771Met	missense	Exon 16 of 50	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.2311G>A	p.Val771Met	missense	Exon 16 of 50	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.2311G>A	p.Val771Met	missense	Exon 16 of 50	ENSP00000504612.1
	ABCA1	ENST00000494467.1	TSL:3	n.484G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8824 AN: 152138 Hom.: 347 Cov.: 33

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0689

GnomAD2 exomes AF: 0.0541 AC: 13584 AN: 250888 AF XY: 0.0518

Gnomad AFR exome AF: 0.0949

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0580

GnomAD4 exome AF: 0.0374 AC: 54721 AN: 1461734 Hom.: 1562 Cov.: 32 AF XY: 0.0379 AC XY: 27543 AN XY: 727174

African (AFR) AF: 0.0892 AC: 2987 AN: 33476

American (AMR) AF: 0.136 AC: 6063 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0492 AC: 1286 AN: 26136

East Asian (EAS) AF: 0.0426 AC: 1691 AN: 39700

South Asian (SAS) AF: 0.0640 AC: 5516 AN: 86252

European-Finnish (FIN) AF: 0.0160 AC: 854 AN: 53364

Middle Eastern (MID) AF: 0.0937 AC: 536 AN: 5718

European-Non Finnish (NFE) AF: 0.0297 AC: 32998 AN: 1111976

Other (OTH) AF: 0.0462 AC: 2790 AN: 60390

GnomAD4 genome AF: 0.0580 AC: 8835 AN: 152256 Hom.: 346 Cov.: 33 AF XY: 0.0585 AC XY: 4360 AN XY: 74476

African (AFR) AF: 0.0945 AC: 3923 AN: 41520

American (AMR) AF: 0.109 AC: 1673 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3470

East Asian (EAS) AF: 0.0272 AC: 141 AN: 5188

South Asian (SAS) AF: 0.0632 AC: 305 AN: 4824

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10618

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2145 AN: 68020

Other (OTH) AF: 0.0691 AC: 146 AN: 2112

Alfa AF: 0.0389 Hom.: 411

Bravo AF: 0.0662

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.0915 AC: 403

ESP6500EA AF: 0.0363 AC: 312

ExAC AF: 0.0512 AC: 6210

EpiCase AF: 0.0365

EpiControl AF: 0.0344

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypoalphalipoproteinemia, primary, 1 (1)
-	-	1	Tangier disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.097
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.47	N
PhyloP100		1.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.18
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.074	B
Vest4		0.086
MPC		0.27
ClinPred		0.0074	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.33
Mutation Taster		=92/8	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: rs2066718; hg19: chr9-107589255; COSMIC: COSV107489888;