2-202942765-A-T

Variant names:

Variant summary

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

The NM_024744.17(CARF):c.104A>T(p.Asp35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D35N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CARF
NM_024744.17 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

Variant links:

Genes affected

CARF (HGNC:14435): (calcium responsive transcription factor) Enables DNA binding activity and DNA-binding transcription factor activity. Involved in cellular response to potassium ion and positive regulation of transcription from RNA polymerase II promoter in response to calcium ion. Predicted to be located in granular component. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CARF links:

WDR12 (HGNC:14098): (WD repeat domain 12) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein is highly similar to the mouse WD repeat domain 12 protein at the amino acid level. The protein encoded by this gene is a component of a nucleolar protein complex that affects maturation of the large ribosomal subunit.[provided by RefSeq, Dec 2008]

WDR12 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=0.14432764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARF	NM_024744.17 link	c.104A>T	p.Asp35Val	missense_variant	Exon 5 of 17	ENST00000438828.4	NP_079020.13	Q8N187-1A0A024R405

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARF	ENST00000438828.4 link	c.104A>T	p.Asp35Val	missense_variant	Exon 5 of 17	1	NM_024744.17	ENSP00000414644.1		Q8N187-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248986

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135092

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.104A>T (p.D35V) alteration is located in exon 5 (coding exon 2) of the CARF gene. This alteration results from a A to T substitution at nucleotide position 104, causing the aspartic acid (D) at amino acid position 35 to be replaced by a valine (V). 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

Benign

0.12

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.;.;.;.;.;.;.;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.89

.;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.14

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.;.;.;.;M

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

N;D;D;D;D;D;D;D;D;N

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99

D;.;.;D;.;.;.;.;.;D

Vest4

0.50

MutPred

0.34

Loss of disorder (P = 0.0355);Loss of disorder (P = 0.0355);.;Loss of disorder (P = 0.0355);Loss of disorder (P = 0.0355);.;Loss of disorder (P = 0.0355);Loss of disorder (P = 0.0355);Loss of disorder (P = 0.0355);Loss of disorder (P = 0.0355);

MVP

0.22

MPC

0.29

ClinPred

0.76

GERP RS

3.1

Varity_R

0.23

gMVP

0.48

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