rs201084520

Variant names:

• chr19-38404968-C-G
• rs201084520
• NM_174905.4:c.410C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38404968-C-G
• chr19-38404968-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174905.4(FAM98C):​c.410C>G​(p.Pro137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P137L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM98C NM_174905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1483092).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174905.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM98C	NM_174905.4	MANE Select	c.410C>G	p.Pro137Arg	missense	Exon 4 of 8	NP_777565.3
	FAM98C	NM_001351675.1		c.410C>G	p.Pro137Arg	missense	Exon 4 of 6	NP_001338604.1	Q17RN3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM98C	ENST00000252530.10	TSL:1 MANE Select	c.410C>G	p.Pro137Arg	missense	Exon 4 of 8	ENSP00000252530.4	Q17RN3-1
	FAM98C	ENST00000343358.11	TSL:1	c.410C>G	p.Pro137Arg	missense	Exon 4 of 6	ENSP00000340348.6	Q17RN3-2
	FAM98C	ENST00000588262.5	TSL:1	c.349+1274C>G		intron	N/A	ENSP00000467974.1	K7EQT7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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 AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.087
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.026	D
Polyphen		0.82	P
Vest4		0.17
MutPred		0.41		Loss of glycosylation at P137 (P = 0.0103)
MVP		0.34
MPC		0.66
ClinPred		0.59	D
GERP RS		3.5
Varity_R		0.065
gMVP		0.13
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201084520; hg19: chr19-38895608;