rs33918808

Variant names:

• chr9-104817351-C-G
• rs33918808
• NM_005502.4:c.3516G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-104817351-C-G
• chr9-104817351-C-T

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.3516G>C​(p.Glu1172Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,614,132 control chromosomes in the GnomAD database, including 1,919 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. E1172G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.069 (686 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1233 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.898
• Publications: 40 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=0.0016642511).
• BP6: Variant 9-104817351-C-G is Benign according to our data. Variant chr9-104817351-C-G is described in ClinVar as Benign. ClinVar VariationId is 364416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.3516G>C	p.Glu1172Asp	missense	Exon 24 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.3516G>C	p.Glu1172Asp	missense	Exon 24 of 50	ENSP00000363868.3	O95477
	ABCA1	ENST00000678995.1		c.3463-47G>C		intron	N/A	ENSP00000504612.1	A0A7I2V5U0

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10455 AN: 152150 Hom.: 686 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0631

GnomAD2 exomes AF: 0.0348 AC: 8752 AN: 251472 AF XY: 0.0320

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0379

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0353

GnomAD4 exome AF: 0.0323 AC: 47163 AN: 1461864 Hom.: 1233 Cov.: 32 AF XY: 0.0315 AC XY: 22912 AN XY: 727234

African (AFR) AF: 0.177 AC: 5924 AN: 33476

American (AMR) AF: 0.0217 AC: 969 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 1077 AN: 26136

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

South Asian (SAS) AF: 0.0223 AC: 1923 AN: 86254

European-Finnish (FIN) AF: 0.0247 AC: 1321 AN: 53414

Middle Eastern (MID) AF: 0.0678 AC: 391 AN: 5768

European-Non Finnish (NFE) AF: 0.0298 AC: 33170 AN: 1111998

Other (OTH) AF: 0.0395 AC: 2385 AN: 60394

GnomAD4 genome AF: 0.0688 AC: 10471 AN: 152268 Hom.: 686 Cov.: 32 AF XY: 0.0667 AC XY: 4963 AN XY: 74446

African (AFR) AF: 0.173 AC: 7196 AN: 41520

American (AMR) AF: 0.0392 AC: 600 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4832

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0294 AC: 1998 AN: 68028

Other (OTH) AF: 0.0624 AC: 132 AN: 2114

Alfa AF: 0.0345 Hom.: 126

Bravo AF: 0.0735

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.161 AC: 710

ESP6500EA AF: 0.0317 AC: 273

ExAC AF: 0.0382 AC: 4636

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.0322

EpiControl AF: 0.0298

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ABCA1-related disorder (1)
-	-	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	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.90
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.33
Sift	Benign	0.32	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.25		Loss of sheet (P = 0.0315)
MPC		0.34
ClinPred		0.0074	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.45
Mutation Taster		=91/9	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: rs33918808; hg19: chr9-107579632; COSMIC: COSV66065920;