rs2736779

Positions:

• chr3-60081118-G-A
• chr3-60081118-G-C
• chr3-60081118-G-T

Variant summary

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

The NM_002012.4(FHIT):​c.104-66966C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 151,906 control chromosomes in the GnomAD database, including 11,672 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 0.38 (11672 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.104-66966C>T		intron_variant		ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.104-66966C>T		intron_variant		1	NM_002012.4	ENSP00000418582	P1
FHIT	ENST00000476844.5	c.104-66966C>T		intron_variant		1		ENSP00000417557	P1
FHIT	ENST00000468189.5	c.104-66966C>T		intron_variant		2		ENSP00000417480	P1
FHIT	ENST00000488467.5	c.104-66966C>T		intron_variant		3		ENSP00000418596

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57891 AN: 151788 Hom.: 11670 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.381 AC: 57908 AN: 151906 Hom.: 11672 Cov.: 32 AF XY: 0.383 AC XY: 28436 AN XY: 74262

Gnomad4 AFR AF: 0.509

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.453

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.359

Alfa AF: 0.348 Hom.: 1957

Bravo AF: 0.384

Asia WGS AF: 0.370 AC: 1289 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.33

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: rs2736779; hg19: chr3-60066844;