chr3-60010140-T-G

Variant names:

• chr3-60010140-T-G
• rs3915504
• NM_002012.4:c.279+1231A>C

Variant summary

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

The NM_002012.4(FHIT):​c.279+1231A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 152,084 control chromosomes in the GnomAD database, including 27,213 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 0.60 (27213 hom., cov: 33)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.160
• Publications: 3 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 (SAS) allele frequency at 95% confidence interval = 0.718 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	NM_002012.4	MANE Select	c.279+1231A>C		intron	N/A	NP_002003.1
	FHIT	NM_001166243.3		c.279+1231A>C		intron	N/A	NP_001159715.1
	FHIT	NM_001320899.2		c.279+1231A>C		intron	N/A	NP_001307828.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.279+1231A>C		intron	N/A	ENSP00000418582.1
	FHIT	ENST00000476844.5	TSL:1	c.279+1231A>C		intron	N/A	ENSP00000417557.1
	FHIT	ENST00000468189.5	TSL:2	c.279+1231A>C		intron	N/A	ENSP00000417480.1

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90588 AN: 151966 Hom.: 27202 Cov.: 33

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.600

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

GnomAD4 genome AF: 0.596 AC: 90640 AN: 152084 Hom.: 27213 Cov.: 33 AF XY: 0.598 AC XY: 44450 AN XY: 74356

African (AFR) AF: 0.539 AC: 22352 AN: 41484

American (AMR) AF: 0.532 AC: 8128 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2681 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2456 AN: 5180

South Asian (SAS) AF: 0.738 AC: 3562 AN: 4824

European-Finnish (FIN) AF: 0.637 AC: 6733 AN: 10578

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42679 AN: 67960

Other (OTH) AF: 0.604 AC: 1275 AN: 2112

Alfa AF: 0.629 Hom.: 17766

Bravo AF: 0.580

Asia WGS AF: 0.580 AC: 2015 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	2.5
DANN	Benign	0.68
PhyloP100		-0.16
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: rs3915504; hg19: chr3-59995866;