Genetic Variant FSCB:p.Ala666Thr (chr14-44504992-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032135.4(FSCB):c.1996G>A(p.Ala666Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,419,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

FSCB
NM_032135.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00700

Publications

0 publications found

Variant links:

Genes affected

FSCB (HGNC:20494): (fibrous sheath CABYR binding protein) Predicted to enable calcium ion binding activity. Predicted to be involved in negative regulation of protein sumoylation. Predicted to be active in sperm fibrous sheath and sperm principal piece. [provided by Alliance of Genome Resources, Apr 2022]

FSCB links:

LINC02277 (HGNC:53193): (long intergenic non-protein coding RNA 2277)

LINC02277 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10225156).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032135.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSCB	NM_032135.4	MANE Select	c.1996G>A	p.Ala666Thr	missense	Exon 1 of 1	NP_115511.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FSCB	ENST00000340446.5	TSL:6 MANE Select	c.1996G>A	p.Ala666Thr	missense	Exon 1 of 1	ENSP00000344579.4	Q5H9T9
LINC02277	ENST00000557721.2	TSL:2	n.108-60170G>A		intron	N/A
LINC02277	ENST00000795526.1		n.108-60170G>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000566

AC:

AN:

176554

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000130

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000352

AC:

AN:

1419290

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31756

American (AMR)

AF:

0.00

AC:

AN:

39442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24466

East Asian (EAS)

AF:

0.00

AC:

AN:

37594

South Asian (SAS)

AF:

0.00

AC:

AN:

80592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.00000458

AC:

AN:

1092430

Other (OTH)

AF:

0.00

AC:

AN:

58410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.24

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0038

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.51

M_CAP

Benign

0.0027

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

-0.0070

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.85

REVEL

Benign

0.045

Sift

Benign

0.26

Sift4G

Benign

0.51

Polyphen

0.94

Vest4

0.042

MutPred

0.22

Gain of phosphorylation at A666 (P = 0.0026)

MVP

0.067

MPC

0.013

ClinPred

0.42

GERP RS

2.6

Varity_R

0.026

gMVP

0.039

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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