dbSNP rs372774526: CACFD1:p.Ser34Tyr (chr9-133460167-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017586.5(CACFD1):c.101C>A(p.Ser34Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,402,940 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. S34C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CACFD1
NM_017586.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.40

Publications

0 publications found

Variant links:

Genes affected

CACFD1 (HGNC:1365): (calcium channel flower domain containing 1) Predicted to be involved in vesicle-mediated transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CACFD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017586.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACFD1	NM_017586.5	MANE Select	c.101C>A	p.Ser34Tyr	missense	Exon 1 of 5	NP_060056.1	Q9UGQ2-1
CACFD1	NM_001242369.2		c.101C>A	p.Ser34Tyr	missense	Exon 1 of 6	NP_001229298.1	Q9UGQ2-4
CACFD1	NM_001242370.2		c.101C>A	p.Ser34Tyr	missense	Exon 1 of 5	NP_001229299.1	Q9UGQ2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACFD1	ENST00000316948.9	TSL:1 MANE Select	c.101C>A	p.Ser34Tyr	missense	Exon 1 of 5	ENSP00000317121.4	Q9UGQ2-1
CACFD1	ENST00000540581.5	TSL:2	c.101C>A	p.Ser34Tyr	missense	Exon 1 of 6	ENSP00000440832.1	Q9UGQ2-4
CACFD1	ENST00000542192.5	TSL:2	c.101C>A	p.Ser34Tyr	missense	Exon 1 of 5	ENSP00000444328.1	Q9UGQ2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402940

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692966

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000319

AC:

AN:

31366

American (AMR)

AF:

0.00

AC:

AN:

36884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

36116

South Asian (SAS)

AF:

0.00

AC:

AN:

80010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5414

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081918

Other (OTH)

AF:

0.00

AC:

AN:

58108

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

Eigen

Benign

-0.053

Eigen_PC

Benign

0.022

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.0

PhyloP100

6.4

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.59

REVEL

Benign

0.19

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0050

Polyphen

0.51

Vest4

0.33

MutPred

0.54

Gain of helix (P = 0.0325)

MVP

0.62

MPC

0.20

ClinPred

0.57

GERP RS

4.2

PromoterAI

0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.71

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over