Genetic Variant NM_174905.4:c.190G>A (chr19-38403462-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_174905.4(FAM98C):c.190G>A(p.Ala64Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,405,082 control chromosomes in the GnomAD database, including 853 homozygotes. 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 Benign (no stars).

Frequency

Genomes: 𝑓 0.024 ( 121 hom., cov: 32)

Exomes 𝑓: 0.022 ( 732 hom. )

Consequence

FAM98C
NM_174905.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.722

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011990964).

BP6

Variant 19-38403462-G-A is Benign according to our data. Variant chr19-38403462-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059360.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

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.190G>A	p.Ala64Thr	missense	Exon 2 of 8	NP_777565.3
	FAM98C	NM_001351675.1		c.190G>A	p.Ala64Thr	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.190G>A	p.Ala64Thr	missense	Exon 2 of 8	ENSP00000252530.4	Q17RN3-1
FAM98C	ENST00000343358.11	TSL:1	c.190G>A	p.Ala64Thr	missense	Exon 2 of 6	ENSP00000340348.6	Q17RN3-2
FAM98C	ENST00000588262.5	TSL:1	c.190G>A	p.Ala64Thr	missense	Exon 2 of 5	ENSP00000467974.1	K7EQT7

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3722

AN:

152190

Hom.:

122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00629

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0830

Gnomad ASJ

AF:

0.0302

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.0105

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0492

AC:

860

AN:

17476

AF XY:

0.0426

show subpopulations

Gnomad AFR exome

AF:

0.00488

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.157

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0394

GnomAD4 exome

AF:

0.0224

AC:

28109

AN:

1252784

Hom.:

732

Cov.:

AF XY:

0.0222

AC XY:

13546

AN XY:

611412

show subpopulations

African (AFR)

AF:

0.00473

AC:

115

AN:

24296

American (AMR)

AF:

0.114

AC:

1417

AN:

12386

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

474

AN:

18226

East Asian (EAS)

AF:

0.163

AC:

4581

AN:

28130

South Asian (SAS)

AF:

0.00992

AC:

595

AN:

59958

European-Finnish (FIN)

AF:

0.0146

AC:

444

AN:

30428

Middle Eastern (MID)

AF:

0.0186

AC:

AN:

4354

European-Non Finnish (NFE)

AF:

0.0187

AC:

19096

AN:

1023176

Other (OTH)

AF:

0.0252

AC:

1306

AN:

51830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1900

3800

5699

7599

9499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.0244

AC:

3723

AN:

152298

Hom.:

121

Cov.:

AF XY:

0.0259

AC XY:

1925

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00630

AC:

262

AN:

41586

American (AMR)

AF:

0.0830

AC:

1271

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

105

AN:

3472

East Asian (EAS)

AF:

0.119

AC:

615

AN:

5148

South Asian (SAS)

AF:

0.0106

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10630

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0175

AC:

1190

AN:

68004

Other (OTH)

AF:

0.0326

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

194

388

582

776

970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0248

Hom.:

Bravo

AF:

0.0302

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00464

AC:

ESP6500EA

AF:

0.0147

AC:

ExAC

AF:

0.0146

AC:

1069

Asia WGS

AF:

0.0590

AC:

203

AN:

3468

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

FAM98C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0065

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

0.72

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.28

REVEL

Benign

0.016

Sift

Benign

0.35

Sift4G

Benign

0.83

Polyphen

0.0060

Vest4

0.12

MPC

1.2

ClinPred

0.0022

GERP RS

2.0

PromoterAI

0.031

Neutral

(source)

Varity_R

0.034

gMVP

0.11

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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