rs1040336

Positions:

• chr3-60089466-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002012.4(FHIT):​c.104-75314A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 151,890 control chromosomes in the GnomAD database, including 4,004 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 0.21 (4004 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.104-75314A>G		intron_variant		ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.104-75314A>G		intron_variant		1	NM_002012.4	ENSP00000418582	P1
FHIT	ENST00000476844.5	c.104-75314A>G		intron_variant		1		ENSP00000417557	P1
FHIT	ENST00000468189.5	c.104-75314A>G		intron_variant		2		ENSP00000417480	P1
FHIT	ENST00000488467.5	c.104-75314A>G		intron_variant		3		ENSP00000418596

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31965 AN: 151772 Hom.: 3989 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.211 AC: 32022 AN: 151890 Hom.: 4004 Cov.: 32 AF XY: 0.217 AC XY: 16108 AN XY: 74228

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.252

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.210

Alfa AF: 0.174 Hom.: 5301

Bravo AF: 0.215

Asia WGS AF: 0.394 AC: 1370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.7
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs1040336; hg19: chr3-60075192;