Genetic Variant C4orf54:p.Glu875Gln (chr4-99652026-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001354435.2(C4orf54):c.2623G>C(p.Glu875Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0123 in 1,536,122 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0095 ( 12 hom., cov: 32)

Exomes 𝑓: 0.013 ( 140 hom. )

Consequence

C4orf54
NM_001354435.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.98

Variant links:

Genes affected

C4orf54 (HGNC:27741): (chromosome 4 open reading frame 54)

C4orf54 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00588125).

BP6

Variant 4-99652026-C-G is Benign according to our data. Variant chr4-99652026-C-G is described in ClinVar as [Benign]. Clinvar id is 2654972.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C4orf54	NM_001354435.2 link	c.2623G>C	p.Glu875Gln	missense_variant	Exon 2 of 3	ENST00000511828.2	NP_001341364.1
C4orf54	XM_373030.12 link	c.2722G>C	p.Glu908Gln	missense_variant	Exon 2 of 3		XP_373030.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C4orf54	ENST00000511828.2 link	c.2623G>C	p.Glu875Gln	missense_variant	Exon 2 of 3	1	NM_001354435.2	ENSP00000427555.1		D6RIA3

Frequencies

GnomAD3 genomes

AF:

0.00950

AC:

1446

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.0220

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0100

AC:

1347

AN:

134578

Hom.:

AF XY:

0.0107

AC XY:

783

AN XY:

73302

show subpopulations

Gnomad AFR exome

AF:

0.00217

Gnomad AMR exome

AF:

0.00813

Gnomad ASJ exome

AF:

0.0188

Gnomad EAS exome

AF:

0.000762

Gnomad SAS exome

AF:

0.00685

Gnomad FIN exome

AF:

0.0241

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0150

GnomAD4 exome

AF:

0.0126

AC:

17416

AN:

1383818

Hom.:

140

Cov.:

AF XY:

0.0124

AC XY:

8458

AN XY:

682848

show subpopulations

Gnomad4 AFR exome

AF:

0.00177

Gnomad4 AMR exome

AF:

0.00829

Gnomad4 ASJ exome

AF:

0.0200

Gnomad4 EAS exome

AF:

0.000532

Gnomad4 SAS exome

AF:

0.00755

Gnomad4 FIN exome

AF:

0.0221

Gnomad4 NFE exome

AF:

0.0133

Gnomad4 OTH exome

AF:

0.0129

GnomAD4 genome

AF:

0.00953

AC:

1451

AN:

152304

Hom.:

Cov.:

AF XY:

0.00937

AC XY:

698

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0220

Gnomad4 NFE

AF:

0.0124

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00832

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0119

AC:

ExAC

AF:

0.00678

AC:

116

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

C4orf54: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

Eigen

Benign

0.12

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0059

MetaSVM

Benign

-0.89

PROVEAN

Benign

0.14

REVEL

Benign

0.084

Sift

Uncertain

0.0090

Sift4G

Benign

0.12

Vest4

0.17

MVP

0.17

ClinPred

0.034

GERP RS

4.5

Varity_R

0.14

gMVP

0.21

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

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