NM_033449.3:c.2062C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033449.3(FCHSD1):​c.2062C>T​(p.Pro688Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,502,726 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: FCHSD1 NM_033449.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010565221).

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>T	p.Pro688Ser	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>T	p.Pro688Ser	missense	Exon 20 of 20	ENSP00000399259.2	Q86WN1-1
	FCHSD1	ENST00000896539.1		c.2170C>T	p.Pro724Ser	missense	Exon 20 of 20	ENSP00000566598.1
	FCHSD1	ENST00000896537.1		c.2056C>T	p.Pro686Ser	missense	Exon 20 of 20	ENSP00000566596.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000548 AC: 8 AN: 146006 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 24 AN: 1350404 Hom.: 0 Cov.: 30 AF XY: 0.0000182 AC XY: 12 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: 0.000367 AC: 14 AN: 38168

South Asian (SAS) AF: 0.0000442 AC: 3 AN: 67848

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

Middle Eastern (MID) AF: 0.000416 AC: 2 AN: 4802

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1058214

Other (OTH) AF: 0.0000539 AC: 3 AN: 55632

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74484

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

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000500 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.9
DANN	Benign	0.86
DEOGEN2	Benign	0.00088	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.31
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.022
Sift	Benign	0.25	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.036
MVP		0.23
MPC		0.15
ClinPred		0.011	T
GERP RS		-0.055
Varity_R		0.080
gMVP		0.24
Mutation Taster		=96/4	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;