chr3-60733690-T-C

Variant names:

• chr3-60733690-T-C
• rs1716741
• NM_002012.4:c.-18+88229A>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+88229A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,200 control chromosomes in the GnomAD database, including 2,052 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 0.15 (2052 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.686
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-18+88229A>G		intron_variant	Intron 4 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.-18+88229A>G		intron_variant	Intron 4 of 9	1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23052 AN: 152082 Hom.: 2050 Cov.: 32

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.0559

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.152 AC: 23071 AN: 152200 Hom.: 2052 Cov.: 32 AF XY: 0.152 AC XY: 11293 AN XY: 74398

African (AFR) AF: 0.0670 AC: 2783 AN: 41546

American (AMR) AF: 0.187 AC: 2852 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3470

East Asian (EAS) AF: 0.0562 AC: 291 AN: 5176

South Asian (SAS) AF: 0.113 AC: 546 AN: 4826

European-Finnish (FIN) AF: 0.212 AC: 2246 AN: 10572

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12982 AN: 68018

Other (OTH) AF: 0.178 AC: 376 AN: 2114

Alfa AF: 0.177 Hom.: 5685

Bravo AF: 0.147

Asia WGS AF: 0.102 AC: 355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.4
DANN	Benign	0.70
PhyloP100		0.69
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: rs1716741; hg19: chr3-60719423;