dbSNP rs1465252573: FAM98C:p.Gly22Arg (chr19-38403217-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_174905.4(FAM98C):c.64G>A(p.Gly22Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM98C
NM_174905.4 missense, splice_region

Scores

Splicing: ADA: 0.8168

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.46

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

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.64G>A	p.Gly22Arg	missense splice_region	Exon 1 of 8	NP_777565.3
	FAM98C	NM_001351675.1		c.64G>A	p.Gly22Arg	missense splice_region	Exon 1 of 6	NP_001338604.1	Q17RN3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM98C	ENST00000252530.10	TSL:1 MANE Select	c.64G>A	p.Gly22Arg	missense splice_region	Exon 1 of 8	ENSP00000252530.4	Q17RN3-1
FAM98C	ENST00000343358.11	TSL:1	c.64G>A	p.Gly22Arg	missense splice_region	Exon 1 of 6	ENSP00000340348.6	Q17RN3-2
FAM98C	ENST00000588262.5	TSL:1	c.64G>A	p.Gly22Arg	missense splice_region	Exon 1 of 5	ENSP00000467974.1	K7EQT7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406646

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699420

African (AFR)

AF:

0.00

AC:

AN:

29004

American (AMR)

AF:

0.00

AC:

AN:

36236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24626

East Asian (EAS)

AF:

0.00

AC:

AN:

33666

South Asian (SAS)

AF:

0.00

AC:

AN:

80250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091888

Other (OTH)

AF:

0.00

AC:

AN:

58150

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000334

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.0

PhyloP100

4.5

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.52

MutPred

0.86

Gain of solvent accessibility (P = 0.0055)

MVP

0.62

MPC

2.6

ClinPred

0.99

GERP RS

4.3

PromoterAI

0.088

Neutral

(source)

Varity_R

0.30

gMVP

0.71

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Benign

0.61

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over