19-38403685-C-G

Position:

• chr19-38403685-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_174905.4(FAM98C):​c.340C>G​(p.Arg114Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,108 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: FAM98C NM_174905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM98C	NM_174905.4	c.340C>G	p.Arg114Gly	missense_variant	3/8	ENST00000252530.10	NP_777565.3
FAM98C	NM_001351675.1	c.340C>G	p.Arg114Gly	missense_variant	3/6		NP_001338604.1
FAM98C	XM_017026354.2	c.340C>G	p.Arg114Gly	missense_variant	3/6		XP_016881843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM98C	ENST00000252530.10	c.340C>G	p.Arg114Gly	missense_variant	3/8	1	NM_174905.4	ENSP00000252530.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.340C>G (p.R114G) alteration is located in exon 3 (coding exon 3) of the FAM98C gene. This alteration results from a C to G substitution at nucleotide position 340, causing the arginine (R) at amino acid position 114 to be replaced by a glycine (G). 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	0.22
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.7	.;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	.;D;D
REVEL	Benign	0.28
Sift	Benign	0.059	.;T;T
Sift4G	Pathogenic	0.0	D;T;D
Polyphen		0.98, 1.0	.;D;D
Vest4		0.48
MutPred		0.66		Loss of methylation at R114 (P = 0.0332);Loss of methylation at R114 (P = 0.0332);Loss of methylation at R114 (P = 0.0332);
MVP		0.62
MPC		1.8
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.55
gMVP		0.36

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

Other links and lift over

dbSNP: rs1568400662; hg19: chr19-38894325;