Genetic Variant FNDC3A:p.Ile18Thr (chr13-49006243-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001079673.2(FNDC3A):c.53T>C(p.Ile18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,610,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FNDC3A
NM_001079673.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Variant links:

Genes affected

FNDC3A (HGNC:20296): (fibronectin type III domain containing 3A) Enables RNA binding activity. Predicted to act upstream of or within several processes, including Sertoli cell development; fertilization; and spermatid development. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

FNDC3A links:

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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=0.25939798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNDC3A	NM_001079673.2 link	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 26	ENST00000492622.6	NP_001073141.1	Q9Y2H6-1A0A024RDT9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FNDC3A	ENST00000492622.6 link	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 26	1	NM_001079673.2	ENSP00000417257.1	Q9Y2H6-1
FNDC3A	ENST00000541916.5 link	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 26	1		ENSP00000441831.1	Q9Y2H6-1
FNDC3A	ENST00000484074.5 link	n.53T>C		non_coding_transcript_exon_variant	Exon 2 of 26	1		ENSP00000420275.1	G5E9X3
FNDC3A	ENST00000378383.5 link	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 8	2		ENSP00000484320.1	A0A087X1M6

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152036

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248500

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134926

show subpopulations

Gnomad AFR exome

AF:

0.000130

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458242

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725636

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74278

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:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53T>C (p.I18T) alteration is located in exon 2 (coding exon 1) of the FNDC3A gene. This alteration results from a T to C substitution at nucleotide position 53, causing the isoleucine (I) at amino acid position 18 to be replaced by a threonine (T). 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.77

.;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.;M

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.81

N;.;N

REVEL

Benign

0.17

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.49

P;.;P

Vest4

0.53

MVP

0.46

MPC

0.53

ClinPred

0.52

GERP RS

5.3

Varity_R

0.15

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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