19-38405522-G-A

Position:

• chr19-38405522-G-A

Variant summary

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

The NM_174905.4(FAM98C):​c.637G>A​(p.Ala213Thr) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A213A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM98C NM_174905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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]

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=0.25917107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM98C	NM_174905.4	c.637G>A	p.Ala213Thr	missense_variant	6/8	ENST00000252530.10
FAM98C	NM_001351675.1	c.559G>A	p.Ala187Thr	missense_variant	5/6
FAM98C	XM_017026354.2	c.*18G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM98C	ENST00000252530.10	c.637G>A	p.Ala213Thr	missense_variant	6/8	1	NM_174905.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 01, 2023

The c.637G>A (p.A213T) alteration is located in exon 6 (coding exon 6) of the FAM98C gene. This alteration results from a G to A substitution at nucleotide position 637, causing the alanine (A) at amino acid position 213 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	Benign	0.082
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.74	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.051
Sift	Benign	0.12	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.48	P;P
Vest4		0.36
MutPred		0.43		Gain of phosphorylation at A213 (P = 0.0353);.;
MVP		0.62
MPC		0.67
ClinPred		0.87	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.082

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

Other links and lift over

dbSNP: rs1971026426; hg19: chr19-38896162;