Genetic Variant NM_174905.4:c.64G>C (chr19-38403217-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_174905.4(FAM98C):c.64G>C(p.Gly22Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000173 in 1,558,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

FAM98C
NM_174905.4 missense, splice_region

Scores

Splicing: ADA: 0.9573

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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>C	p.Gly22Arg	missense splice_region	Exon 1 of 8	NP_777565.3
	FAM98C	NM_001351675.1		c.64G>C	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>C	p.Gly22Arg	missense splice_region	Exon 1 of 8	ENSP00000252530.4	Q17RN3-1
FAM98C	ENST00000343358.11	TSL:1	c.64G>C	p.Gly22Arg	missense splice_region	Exon 1 of 6	ENSP00000340348.6	Q17RN3-2
FAM98C	ENST00000588262.5	TSL:1	c.64G>C	p.Gly22Arg	missense splice_region	Exon 1 of 5	ENSP00000467974.1	K7EQT7

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152180

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000108

AC:

AN:

184504

AF XY:

0.0000193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000226

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000156

AC:

AN:

1406650

Hom.:

Cov.:

AF XY:

0.0000157

AC XY:

AN XY:

699422

show subpopulations

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:

47182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

1091890

Other (OTH)

AF:

0.0000172

AC:

AN:

58150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000329

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

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

0.59

BayesDel_addAF

Uncertain

0.035

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

0.74

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.0

PhyloP100

4.5

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.38

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

0.98

GERP RS

4.3

PromoterAI

0.079

Neutral

(source)

Varity_R

0.30

gMVP

0.71

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.12

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over