3-60803137-T-C

Variant names:

• chr3-60803137-T-C
• rs1447925
• NM_002012.4:c.-18+18782A>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.-18+18782A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 152,072 control chromosomes in the GnomAD database, including 36,274 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 0.67 (36274 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 4 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.826 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.-18+18782A>G		intron	N/A	NP_002003.1
	FHIT	NM_001166243.3		c.-18+18782A>G		intron	N/A	NP_001159715.1
	FHIT	NM_001320899.2		c.-18+18782A>G		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.-18+18782A>G		intron	N/A	ENSP00000418582.1
	FHIT	ENST00000476844.5	TSL:1	c.-18+18782A>G		intron	N/A	ENSP00000417557.1
	FHIT	ENST00000490952.1	TSL:1	n.550+18782A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101743 AN: 151954 Hom.: 36282 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.758

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.722

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

GnomAD4 genome AF: 0.669 AC: 101764 AN: 152072 Hom.: 36274 Cov.: 32 AF XY: 0.671 AC XY: 49883 AN XY: 74342

African (AFR) AF: 0.396 AC: 16420 AN: 41460

American (AMR) AF: 0.714 AC: 10911 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2770 AN: 3470

East Asian (EAS) AF: 0.847 AC: 4375 AN: 5166

South Asian (SAS) AF: 0.731 AC: 3515 AN: 4808

European-Finnish (FIN) AF: 0.758 AC: 8022 AN: 10586

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.783 AC: 53273 AN: 67996

Other (OTH) AF: 0.718 AC: 1513 AN: 2106

Alfa AF: 0.740 Hom.: 101431

Bravo AF: 0.669

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
PhyloP100		-0.066

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1447925; hg19: chr3-60788842;