Genetic Variant CD46:c.476-41A>T (chr1-207761208-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172351.3(CD46):c.476-41A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,319,276 control chromosomes in the GnomAD database, including 2,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.044 ( 199 hom., cov: 32)

Exomes 𝑓: 0.063 ( 2617 hom. )

Consequence

CD46
NM_172351.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.169

Variant links:

Genes affected

CD46 (HGNC:6953): (CD46 molecule) The protein encoded by this gene is a type I membrane protein and is a regulatory part of the complement system. The encoded protein has cofactor activity for inactivation of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement. In addition, the encoded protein can act as a receptor for the Edmonston strain of measles virus, human herpesvirus-6, and type IV pili of pathogenic Neisseria. Finally, the protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization. Mutations at this locus have been associated with susceptibility to hemolytic uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CD46 links:

MIR29B2CHG (HGNC:32018): (MIR29B2 and MIR29C host gene)

MIR29B2CHG links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 1-207761208-A-T is Benign according to our data. Variant chr1-207761208-A-T is described in ClinVar as [Benign]. Clinvar id is 1271165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD46	NM_172351.3 link	c.476-41A>T		intron_variant	Intron 4 of 12	ENST00000367042.6	NP_758861.1	P15529-11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6 link	c.476-41A>T		intron_variant	Intron 4 of 12	1	NM_172351.3	ENSP00000356009.1		P15529-11

Frequencies

GnomAD3 genomes

AF:

0.0437

AC:

6652

AN:

152210

Hom.:

198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00615

Gnomad SAS

AF:

0.0463

Gnomad FIN

AF:

0.0479

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0691

Gnomad OTH

AF:

0.0406

GnomAD3 exomes

AF:

0.0455

AC:

9165

AN:

201428

Hom.:

281

AF XY:

0.0468

AC XY:

5084

AN XY:

108736

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.0282

Gnomad ASJ exome

AF:

0.0270

Gnomad EAS exome

AF:

0.00485

Gnomad SAS exome

AF:

0.0476

Gnomad FIN exome

AF:

0.0464

Gnomad NFE exome

AF:

0.0651

Gnomad OTH exome

AF:

0.0452

GnomAD4 exome

AF:

0.0628

AC:

73306

AN:

1166948

Hom.:

2617

Cov.:

AF XY:

0.0619

AC XY:

36585

AN XY:

591378

show subpopulations

Gnomad4 AFR exome

AF:

0.00949

Gnomad4 AMR exome

AF:

0.0292

Gnomad4 ASJ exome

AF:

0.0262

Gnomad4 EAS exome

AF:

0.00451

Gnomad4 SAS exome

AF:

0.0472

Gnomad4 FIN exome

AF:

0.0532

Gnomad4 NFE exome

AF:

0.0725

Gnomad4 OTH exome

AF:

0.0515

GnomAD4 genome

AF:

0.0437

AC:

6652

AN:

152328

Hom.:

199

Cov.:

AF XY:

0.0419

AC XY:

3120

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.0347

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.00617

Gnomad4 SAS

AF:

0.0466

Gnomad4 FIN

AF:

0.0479

Gnomad4 NFE

AF:

0.0691

Gnomad4 OTH

AF:

0.0397

Alfa

AF:

0.0510

Hom.:

Bravo

AF:

0.0398

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.0

DANN

Benign

0.90

BranchPoint Hunter

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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