1-207761208-A-T

Position:

• chr1-207761208-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.169

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 1 / 10). 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/exons	MANE	Protein	UniProt
CD46	NM_172351.3	c.476-41A>T		intron_variant		ENST00000367042.6	NP_758861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6	c.476-41A>T		intron_variant		1	NM_172351.3	ENSP00000356009.1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6652 AN: 152210 Hom.: 198 Cov.: 32

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

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.: 16 AF XY: 0.0619 AC XY: 36585 AN XY: 591378

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.: 32 AF XY: 0.0419 AC XY: 3120 AN XY: 74494

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.: 42

Bravo AF: 0.0398

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2021	- -

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

Other links and lift over

dbSNP: rs41258244; hg19: chr1-207934553;