1-207761264-C-T

Variant names:

• chr1-207761264-C-T
• rs746757476
• NM_172351.3:c.491C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_172351.3(CD46):​c.491C>T​(p.Pro164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,454,926 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P164Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CD46 NM_172351.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_172351.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD46	NM_172351.3	c.491C>T	p.Pro164Leu	missense_variant	Exon 5 of 13	ENST00000367042.6	NP_758861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6	c.491C>T	p.Pro164Leu	missense_variant	Exon 5 of 13	1	NM_172351.3	ENSP00000356009.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1454926 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 724248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;.;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;.;D;D
Vest4		0.46
MutPred		0.60		Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);.;Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);
MVP		0.81
MPC		0.65
ClinPred		0.97	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs746757476; hg19: chr1-207934609;