3-60014014-G-T

Variant names:

• chr3-60014014-G-T
• rs746933635
• NM_002012.4:c.242C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002012.4(FHIT):​c.242C>A​(p.Ser81Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S81C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FHIT NM_002012.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.07
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.242C>A	p.Ser81Tyr	missense	Exon 6 of 10	NP_002003.1	P49789
	FHIT	NM_001166243.3		c.242C>A	p.Ser81Tyr	missense	Exon 6 of 10	NP_001159715.1	P49789
	FHIT	NM_001320899.2		c.242C>A	p.Ser81Tyr	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.242C>A	p.Ser81Tyr	missense	Exon 6 of 10	ENSP00000418582.1	P49789
	FHIT	ENST00000476844.5	TSL:1	c.242C>A	p.Ser81Tyr	missense	Exon 6 of 10	ENSP00000417557.1	P49789
	FHIT	ENST00000468189.5	TSL:2	c.242C>A	p.Ser81Tyr	missense	Exon 6 of 9	ENSP00000417480.1	P49789

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461614 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	2.0	M
PhyloP100		5.1
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.93	P
Vest4		0.72
MutPred		0.48		Loss of disorder (P = 0.0131)
MVP		0.95
MPC		0.052
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		0.0051	Neutral
Varity_R		0.61
gMVP		0.53
Mutation Taster		=49/51	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

dbSNP: rs746933635; hg19: chr3-59999740;