Variant 4-158669744-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001008393.4(C4orf46):c.211C>A(p.Leu71Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,604,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

C4orf46
NM_001008393.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40

Variant links:

Genes affected

C4orf46 (HGNC:27320): (chromosome 4 open reading frame 46) This gene encodes a small, conserved protein of unknown function that is expressed in a variety of tissues. There are pseudogenes for this gene on chromosomes 6, 8, 16, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

C4orf46 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08475253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
C4orf46	NM_001008393.4 linkuse as main transcript	c.211C>A	p.Leu71Ile	missense_variant	2/2	ENST00000379205.5	NP_001008394.1
C4orf46	NR_077234.2 linkuse as main transcript	n.85C>A		non_coding_transcript_exon_variant	2/2
C4orf46	NR_077235.2 linkuse as main transcript	n.81C>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
C4orf46	ENST00000379205.5 linkuse as main transcript	c.211C>A	p.Leu71Ile	missense_variant	2/2	1	NM_001008393.4	ENSP00000368503	P1
C4orf46	ENST00000508836.1 linkuse as main transcript	n.284C>A		non_coding_transcript_exon_variant	2/2	1
C4orf46	ENST00000508457.1 linkuse as main transcript	c.*9C>A		3_prime_UTR_variant	2/2	5		ENSP00000421533

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

240772

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000908

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1452566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000689

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151658

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74018

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.211C>A (p.L71I) alteration is located in exon 2 (coding exon 2) of the C4orf46 gene. This alteration results from a C to A substitution at nucleotide position 211, causing the leucine (L) at amino acid position 71 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.60

M_CAP

Benign

0.0055

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

MutationTaster

Benign

1.0

D;N

PROVEAN

Benign

-1.9

REVEL

Benign

0.14

Sift

Uncertain

0.026

Sift4G

Pathogenic

0.0

Polyphen

0.033

Vest4

0.17

MutPred

0.20

Loss of ubiquitination at K69 (P = 0.0816);

MVP

0.17

MPC

0.89

ClinPred

0.30

GERP RS

3.2

Varity_R

0.15

gMVP

0.067

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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