5-141644220-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033449.3(FCHSD1):c.1861C>A(p.Gln621Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000064 in 1,609,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

FCHSD1
NM_033449.3 missense, splice_region

Scores

Splicing: ADA: 0.02367

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.264

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06874591).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCHSD1	NM_033449.3 linkuse as main transcript	c.1861C>A	p.Gln621Lys	missense_variant, splice_region_variant	17/20	ENST00000435817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCHSD1	ENST00000435817.7 linkuse as main transcript	c.1861C>A	p.Gln621Lys	missense_variant, splice_region_variant	17/20	1	NM_033449.3	P1	Q86WN1-1
FCHSD1	ENST00000522783.5 linkuse as main transcript	c.1639C>A	p.Gln547Lys	missense_variant, splice_region_variant	16/20	5
FCHSD1	ENST00000523856.5 linkuse as main transcript	n.1530C>A		splice_region_variant, non_coding_transcript_exon_variant	8/11	2
FCHSD1	ENST00000522126.5 linkuse as main transcript	c.*399C>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	16/19	2			Q86WN1-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000541

AC:

AN:

240464

Hom.:

AF XY:

0.0000536

AC XY:

AN XY:

130586

show subpopulations

Gnomad AFR exome

AF:

0.0000677

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000686

AC:

100

AN:

1457696

Hom.:

Cov.:

AF XY:

0.0000704

AC XY:

AN XY:

724774

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

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:

0.0000766

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000993

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

Jul 29, 2023

The c.1861C>A (p.Q621K) alteration is located in exon 17 (coding exon 17) of the FCHSD1 gene. This alteration results from a C to A substitution at nucleotide position 1861, causing the glutamine (Q) at amino acid position 621 to be replaced by a lysine (K). 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

0.097

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.54

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.015

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.069

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.023

Sift

Uncertain

0.023

D;T

Sift4G

Benign

0.56

T;D

Polyphen

0.15

B;.

Vest4

0.19

MVP

0.47

MPC

0.25

ClinPred

0.050

GERP RS

2.4

Varity_R

0.14

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.024

dbscSNV1_RF

Benign

0.19

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

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