chr19-38403217-G-T

Variant names:

• chr19-38403217-G-T
• rs1465252573
• NM_174905.4:c.64G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_174905.4(FAM98C):​c.64G>T​(p.Gly22Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000711 in 1,406,650 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G22R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FAM98C NM_174905.4 missense, splice_region
• Scores: Splicing: ADA: 0.9910
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• 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 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>T	p.Gly22Trp	missense splice_region	Exon 1 of 8	NP_777565.3
	FAM98C	NM_001351675.1		c.64G>T	p.Gly22Trp	missense splice_region	Exon 1 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.64G>T	p.Gly22Trp	missense splice_region	Exon 1 of 8	ENSP00000252530.4	Q17RN3-1
	FAM98C	ENST00000343358.11	TSL:1	c.64G>T	p.Gly22Trp	missense splice_region	Exon 1 of 6	ENSP00000340348.6	Q17RN3-2
	FAM98C	ENST00000588262.5	TSL:1	c.64G>T	p.Gly22Trp	missense splice_region	Exon 1 of 5	ENSP00000467974.1	K7EQT7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406650 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 699422

African (AFR) AF: 0.0000345 AC: 1 AN: 29004

American (AMR) AF: 0.00 AC: 0 AN: 36236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24626

East Asian (EAS) AF: 0.00 AC: 0 AN: 33666

South Asian (SAS) AF: 0.00 AC: 0 AN: 80250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091890

Other (OTH) AF: 0.00 AC: 0 AN: 58150

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.90		Loss of disorder (P = 0.0364)
MVP		0.71
MPC		2.6
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		0.012	Neutral
Varity_R		0.39
gMVP		0.72
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.060		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: rs1465252573; hg19: chr19-38893857;