Genetic Variant NM_174905.4:c.128G>A (chr19-38403400-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.128G>A(p.Cys43Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000966 in 1,449,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

FAM98C
NM_174905.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.34

Publications

1 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:

Genome browser will be placed here

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, 0.889

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.128G>A	p.Cys43Tyr	missense	Exon 2 of 8	NP_777565.3
	FAM98C	NM_001351675.1		c.128G>A	p.Cys43Tyr	missense	Exon 2 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.128G>A	p.Cys43Tyr	missense	Exon 2 of 8	ENSP00000252530.4	Q17RN3-1
FAM98C	ENST00000343358.11	TSL:1	c.128G>A	p.Cys43Tyr	missense	Exon 2 of 6	ENSP00000340348.6	Q17RN3-2
FAM98C	ENST00000588262.5	TSL:1	c.128G>A	p.Cys43Tyr	missense	Exon 2 of 5	ENSP00000467974.1	K7EQT7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1297666

Hom.:

Cov.:

AF XY:

0.0000157

AC XY:

AN XY:

638438

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25390

American (AMR)

AF:

0.00

AC:

AN:

15832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21260

East Asian (EAS)

AF:

0.00

AC:

AN:

29196

South Asian (SAS)

AF:

0.0000146

AC:

AN:

68402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4752

European-Non Finnish (NFE)

AF:

0.0000115

AC:

AN:

1045636

Other (OTH)

AF:

0.00

AC:

AN:

53666

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

3.1

PhyloP100

5.3

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.47

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MutPred

0.72

Loss of disorder (P = 0.0934)

MVP

0.63

MPC

3.1

ClinPred

1.0

GERP RS

4.5

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.75

Mutation Taster

=49/51

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over