Genetic Variant FNDC1:p.Ala34Glu (chr6-159169697-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032532.3(FNDC1):c.101C>A(p.Ala34Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000995 in 1,004,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000010 ( 0 hom. )

Consequence

FNDC1
NM_032532.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.212

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:

FNDC1-AS1 (HGNC:55706): (FNDC1 antisense RNA 1)

FNDC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.05272436).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032532.3. 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
	FNDC1	NM_032532.3	MANE Select	c.101C>A	p.Ala34Glu	missense	Exon 1 of 23	NP_115921.2	Q4ZHG4-1
	FNDC1-AS1	NR_121668.1		n.196+115G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FNDC1	ENST00000297267.14	TSL:1 MANE Select	c.101C>A	p.Ala34Glu	missense	Exon 1 of 23	ENSP00000297267.9	Q4ZHG4-1
FNDC1	ENST00000906655.1		c.101C>A	p.Ala34Glu	missense	Exon 1 of 20	ENSP00000576714.1
FNDC1	ENST00000906656.1		c.101C>A	p.Ala34Glu	missense	Exon 1 of 19	ENSP00000576715.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

158

AF XY:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.95e-7

AC:

AN:

1004926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

474286

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

20280

American (AMR)

AF:

0.00

AC:

AN:

6000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11248

East Asian (EAS)

AF:

0.00

AC:

AN:

19628

South Asian (SAS)

AF:

0.00

AC:

AN:

18786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2550

European-Non Finnish (NFE)

AF:

0.00000115

AC:

AN:

870718

Other (OTH)

AF:

0.00

AC:

AN:

38312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0087

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.21

M_CAP

Benign

0.0057

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

PhyloP100

-0.21

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.060

REVEL

Benign

0.0080

Sift

Benign

0.29

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.20

MutPred

0.34

Gain of sheet (P = 0.0125)

MVP

0.35

MPC

0.19

ClinPred

0.19

GERP RS

1.8

PromoterAI

0.091

Neutral

(source)

Varity_R

0.059

gMVP

0.32

Mutation Taster

=99/1

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over