Genetic Variant FAM98C:p.Leu116Met (chr19-38403691-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_174905.4(FAM98C):c.346C>A(p.Leu116Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM98C
NM_174905.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

FAM98C (HGNC:27119): (family with sequence similarity 98 member C) Predicted to be part of tRNA-splicing ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

FAM98C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM98C	NM_174905.4 link	c.346C>A	p.Leu116Met	missense_variant	Exon 3 of 8	ENST00000252530.10	NP_777565.3	Q17RN3-1
FAM98C	NM_001351675.1 link	c.346C>A	p.Leu116Met	missense_variant	Exon 3 of 6		NP_001338604.1
FAM98C	XM_017026354.2 link	c.346C>A	p.Leu116Met	missense_variant	Exon 3 of 6		XP_016881843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM98C	ENST00000252530.10 link	c.346C>A	p.Leu116Met	missense_variant	Exon 3 of 8	1	NM_174905.4	ENSP00000252530.4		Q17RN3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1257136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

612048

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346C>A (p.L116M) alteration is located in exon 3 (coding exon 3) of the FAM98C gene. This alteration results from a C to A substitution at nucleotide position 346, causing the leucine (L) at amino acid position 116 to be replaced by a methionine (M). 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

0.30

BayesDel_addAF

Benign

0.0079

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.43

T;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Uncertain

-0.086

MutationAssessor

Pathogenic

3.3

.;M;M

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.5

.;N;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.0030

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.51

MutPred

0.78

Gain of catalytic residue at L116 (P = 0.0121);Gain of catalytic residue at L116 (P = 0.0121);Gain of catalytic residue at L116 (P = 0.0121);

MVP

0.62

MPC

2.3

ClinPred

0.96

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.30

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

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