19-38403477-G-T

Position:

• chr19-38403477-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174905.4(FAM98C):​c.205G>T​(p.Ala69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,253,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.000018 (0 hom.)
• Consequence: FAM98C NM_174905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18680522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM98C	NM_174905.4	c.205G>T	p.Ala69Ser	missense_variant	2/8	ENST00000252530.10	NP_777565.3
FAM98C	NM_001351675.1	c.205G>T	p.Ala69Ser	missense_variant	2/6		NP_001338604.1
FAM98C	XM_017026354.2	c.205G>T	p.Ala69Ser	missense_variant	2/6		XP_016881843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM98C	ENST00000252530.10	c.205G>T	p.Ala69Ser	missense_variant	2/8	1	NM_174905.4	ENSP00000252530.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000176 AC: 22 AN: 1253524 Hom.: 0 Cov.: 32 AF XY: 0.0000131 AC XY: 8 AN XY: 610990

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: 0.0000215

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 28, 2024

The c.205G>T (p.A69S) alteration is located in exon 2 (coding exon 2) of the FAM98C gene. This alteration results from a G to T substitution at nucleotide position 205, causing the alanine (A) at amino acid position 69 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	.;N;N
REVEL	Benign	0.15
Sift	Benign	0.13	.;T;T
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.88, 0.86	.;P;P
Vest4		0.085
MutPred		0.63		Gain of glycosylation at A69 (P = 0.0016);Gain of glycosylation at A69 (P = 0.0016);Gain of glycosylation at A69 (P = 0.0016);
MVP		0.51
MPC		2.0
ClinPred		0.80	D
GERP RS		2.3
Varity_R		0.071
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1391102612; hg19: chr19-38894117;