5-141643049-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

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]

ACMG classification

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	UniProt
FCHSD1	NM_033449.3	c.1903G>A	p.Ala635Thr	missense_variant	18/20	ENST00000435817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCHSD1	ENST00000435817.7	c.1903G>A	p.Ala635Thr	missense_variant	18/20	1	NM_033449.3	P1
FCHSD1	ENST00000522783.5	c.1681G>A	p.Ala561Thr	missense_variant	17/20	5
FCHSD1	ENST00000523856.5	n.1572G>A		non_coding_transcript_exon_variant	9/11	2
FCHSD1	ENST00000522126.5	c.*402-546G>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393026 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 688844

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.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0014	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.39	T
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	T
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

Other links and lift over

dbSNP: rs781644990; hg19: chr5-141022616;