5-141641509-G-C

Variant names:

• chr5-141641509-G-C
• rs560798832
• NM_033449.3:c.2062C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033449.3(FCHSD1):​c.2062C>G​(p.Pro688Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,350,404 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. 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. P688S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: FCHSD1 NM_033449.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04257384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033449.3. 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
	FCHSD1	NM_033449.3	MANE Select	c.2062C>G	p.Pro688Ala	missense	Exon 20 of 20	NP_258260.1	Q86WN1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCHSD1	ENST00000435817.7	TSL:1 MANE Select	c.2062C>G	p.Pro688Ala	missense	Exon 20 of 20	ENSP00000399259.2	Q86WN1-1
	FCHSD1	ENST00000896539.1		c.2170C>G	p.Pro724Ala	missense	Exon 20 of 20	ENSP00000566598.1
	FCHSD1	ENST00000896537.1		c.2056C>G	p.Pro686Ala	missense	Exon 20 of 20	ENSP00000566596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1350404 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 660024

African (AFR) AF: 0.00 AC: 0 AN: 30206

American (AMR) AF: 0.00 AC: 0 AN: 26830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19798

East Asian (EAS) AF: 0.00 AC: 0 AN: 38168

South Asian (SAS) AF: 0.00 AC: 0 AN: 67848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4802

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058214

Other (OTH) AF: 0.00 AC: 0 AN: 55632

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.7
DANN	Benign	0.88
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.31
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.049
Sift	Benign	0.041	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.23		Loss of glycosylation at T690 (P = 0.1103)
MVP		0.28
MPC		0.14
ClinPred		0.037	T
GERP RS		-0.055
Varity_R		0.078
gMVP		0.17
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs560798832; hg19: chr5-141021076;