rs138880920

Variant names:

• chr9-104826957-C-G
• rs138880920
• NM_005502.4:c.2328G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005502.4(ABCA1):​c.2328G>C​(p.Lys776Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,613,890 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (25 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.18
• Publications: 33 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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=0.036502987).
• BP6: Variant 9-104826957-C-G is Benign according to our data. Variant chr9-104826957-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 364430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00196 (299/152346) while in subpopulation SAS AF = 0.00932 (45/4830). AF 95% confidence interval is 0.00716. There are 0 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.2328G>C	p.Lys776Asn	missense	Exon 16 of 50	NP_005493.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.2328G>C	p.Lys776Asn	missense	Exon 16 of 50	ENSP00000363868.3	O95477
	ABCA1	ENST00000678995.1		c.2328G>C	p.Lys776Asn	missense	Exon 16 of 50	ENSP00000504612.1	A0A7I2V5U0
	ABCA1	ENST00000494467.1	TSL:3	n.501G>C		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00327 AC: 819 AN: 250436 AF XY: 0.00378

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00332

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00276 AC: 4037 AN: 1461544 Hom.: 25 Cov.: 32 AF XY: 0.00296 AC XY: 2151 AN XY: 727062

African (AFR) AF: 0.000418 AC: 14 AN: 33476

American (AMR) AF: 0.00206 AC: 92 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00995 AC: 858 AN: 86244

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53304

Middle Eastern (MID) AF: 0.00996 AC: 56 AN: 5620

European-Non Finnish (NFE) AF: 0.00255 AC: 2835 AN: 1111978

Other (OTH) AF: 0.00245 AC: 148 AN: 60364

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00204 AC XY: 152 AN XY: 74508

African (AFR) AF: 0.000505 AC: 21 AN: 41568

American (AMR) AF: 0.00294 AC: 45 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00223 Hom.: 2

Bravo AF: 0.00202

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00359 AC: 436

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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	Pathogenic	0.92
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.037	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.56		Loss of methylation at K776 (P = 0.0148)
MVP		0.94
MPC		0.70
ClinPred		0.016	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.86
Mutation Taster		=95/5	polymorphism

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: rs138880920; hg19: chr9-107589238;