Variant 5-141643049-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033449.3(FCHSD1):c.1903G>A(p.Ala635Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

FCHSD1
NM_033449.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

Variant links:

Genes affected

FCHSD1 (HGNC:25463): (FCH and double SH3 domains 1) Predicted to enable lipid binding activity. Predicted to be involved in neuromuscular synaptic transmission and positive regulation of actin filament polymerization. Predicted to be located in cell projection and perikaryon. Predicted to be active in neuromuscular junction and recycling endosome. Predicted to colocalize with cuticular plate. [provided by Alliance of Genome Resources, Apr 2022]

FCHSD1 links:

FCHSD1 (HGNC:):

FCHSD1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0504902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCHSD1	NM_033449.3 linkuse as main transcript	c.1903G>A	p.Ala635Thr	missense_variant	18/20	ENST00000435817.7	NP_258260.1	Q86WN1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FCHSD1	ENST00000435817.7 linkuse as main transcript	c.1903G>A	p.Ala635Thr	missense_variant	18/20	1	NM_033449.3	ENSP00000399259.2	Q86WN1-1
FCHSD1	ENST00000522783.5 linkuse as main transcript	c.1681G>A	p.Ala561Thr	missense_variant	17/20	5		ENSP00000428677.1	E5RGT6
FCHSD1	ENST00000523856.5 linkuse as main transcript	n.1572G>A		non_coding_transcript_exon_variant	9/11	2
FCHSD1	ENST00000522126.5 linkuse as main transcript	n.*402-546G>A		intron_variant		2		ENSP00000427796.1	Q86WN1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1393026

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688844

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000834

AC:

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

Oct 25, 2023

The c.1903G>A (p.A635T) alteration is located in exon 18 (coding exon 18) of the FCHSD1 gene. This alteration results from a G to A substitution at nucleotide position 1903, causing the alanine (A) at amino acid position 635 to be replaced by a threonine (T). 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

0.074

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0014

T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.069

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0093

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.49

N;N

REVEL

Benign

0.020

Sift

Benign

0.33

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.084

B;.

Vest4

0.20

MutPred

0.29

Gain of glycosylation at A635 (P = 0.0019);.;

MVP

0.58

MPC

0.19

ClinPred

0.15

GERP RS

4.3

Varity_R

0.030

gMVP

0.20

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