dbSNP rs200234725: FNDC1:p.Glu286Ala (chr6-159223618-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032532.3(FNDC1):c.857A>C(p.Glu286Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E286V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FNDC1
NM_032532.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.53

Publications

0 publications found

Variant links:

Genes affected

FNDC1 (HGNC:21184): (fibronectin type III domain containing 1) Predicted to act upstream of or within several processes, including cellular response to hypoxia; positive regulation of cardiac muscle cell apoptotic process; and positive regulation of protein phosphorylation. Located in nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

FNDC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNDC1	NM_032532.3 link	c.857A>C	p.Glu286Ala	missense_variant	Exon 7 of 23	ENST00000297267.14	NP_115921.2	Q4ZHG4-1
FNDC1	XM_011536190.3 link	c.788A>C	p.Glu263Ala	missense_variant	Exon 6 of 22		XP_011534492.1
FNDC1	XM_011536191.3 link	c.506A>C	p.Glu169Ala	missense_variant	Exon 4 of 20		XP_011534493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FNDC1	ENST00000297267.14 link	c.857A>C	p.Glu286Ala	missense_variant	Exon 7 of 23	1	NM_032532.3	ENSP00000297267.9	Q4ZHG4-1
FNDC1	ENST00000329629.8 link	c.731A>C	p.Glu244Ala	missense_variant	Exon 6 of 21	1		ENSP00000333297.8	J3KNQ2
FNDC1	ENST00000480856.1 link	n.492A>C		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460276

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111042

Other (OTH)

AF:

0.00

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.0038

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.3

PhyloP100

8.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.40

Sift

Uncertain

0.025

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.60

MutPred

0.49

Gain of MoRF binding (P = 0.036);

MVP

0.88

MPC

0.17

ClinPred

0.96

GERP RS

5.8

Varity_R

0.36

gMVP

0.58

Mutation Taster

=39/61

disease causing

(source)

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

Publications

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rs200234725

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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