3-60014062-A-C

Variant names:

• chr3-60014062-A-C
• NM_002012.4:c.194T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002012.4(FHIT):​c.194T>G​(p.Val65Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,772 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FHIT NM_002012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59
• Publications: 0 publications found

Genes affected

FHIT (HGNC:3701): (fragile histidine triad diadenosine triphosphatase) The protein encoded by this gene is a P1-P3-bis(5'-adenosyl) triphosphate hydrolase involved in purine metabolism. This gene encompasses the common fragile site FRA3B on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts. In fact, aberrant transcripts from this gene have been found in about half of all esophageal, stomach, and colon carcinomas. The encoded protein is also a tumor suppressor, as loss of its activity results in replication stress and DNA damage. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002012.4. 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
	FHIT	NM_002012.4	MANE Select	c.194T>G	p.Val65Gly	missense	Exon 6 of 10	NP_002003.1	P49789
	FHIT	NM_001166243.3		c.194T>G	p.Val65Gly	missense	Exon 6 of 10	NP_001159715.1	P49789
	FHIT	NM_001320899.2		c.194T>G	p.Val65Gly	missense	Exon 6 of 9	NP_001307828.1	P49789

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.194T>G	p.Val65Gly	missense	Exon 6 of 10	ENSP00000418582.1	P49789
	FHIT	ENST00000476844.5	TSL:1	c.194T>G	p.Val65Gly	missense	Exon 6 of 10	ENSP00000417557.1	P49789
	FHIT	ENST00000468189.5	TSL:2	c.194T>G	p.Val65Gly	missense	Exon 6 of 9	ENSP00000417480.1	P49789

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111936

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.6
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.84		Loss of stability (P = 2e-04)
MVP		1.0
MPC		0.10
ClinPred		1.0	D
GERP RS		6.0
PromoterAI		-0.026	Neutral
Varity_R		0.95
gMVP		0.70
Mutation Taster		=30/70	disease causing

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

Other links and lift over

hg19: chr3-59999788;