3-59935294-T-C

Variant names:

• chr3-59935294-T-C
• rs4502542
• NM_002012.4:c.280-12880A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002012.4(FHIT):​c.280-12880A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.974 in 152,282 control chromosomes in the GnomAD database, including 72,393 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.97 (72393 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.550
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.280-12880A>G		intron	N/A	NP_002003.1
	FHIT	NM_001166243.3		c.280-12880A>G		intron	N/A	NP_001159715.1
	FHIT	NM_001320899.2		c.280-12880A>G		intron	N/A	NP_001307828.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.280-12880A>G		intron	N/A	ENSP00000418582.1
	FHIT	ENST00000476844.5	TSL:1	c.280-12880A>G		intron	N/A	ENSP00000417557.1
	FHIT	ENST00000468189.5	TSL:2	c.280-12880A>G		intron	N/A	ENSP00000417480.1

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148254 AN: 152164 Hom.: 72339 Cov.: 32

Gnomad AFR AF: 0.912

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.987

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.985

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.974 AC: 148367 AN: 152282 Hom.: 72393 Cov.: 32 AF XY: 0.975 AC XY: 72613 AN XY: 74468

African (AFR) AF: 0.912 AC: 37905 AN: 41544

American (AMR) AF: 0.987 AC: 15089 AN: 15286

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10619 AN: 10622

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67984 AN: 68026

Other (OTH) AF: 0.985 AC: 2082 AN: 2114

Alfa AF: 0.983 Hom.: 65692

Bravo AF: 0.971

Asia WGS AF: 0.995 AC: 3460 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.86
DANN	Benign	0.51
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs4502542; hg19: chr3-59921020;