rs6446101

Positions:

• chr3-59971257-C-G
• chr3-59971257-C-T

Variant summary

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

The NM_002012.4(FHIT):​c.279+40114G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 151,892 control chromosomes in the GnomAD database, including 13,009 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 (13009 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312

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]

FHIT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.279+40114G>C		intron_variant		ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.279+40114G>C		intron_variant		1	NM_002012.4	ENSP00000418582.1
FHIT	ENST00000476844.5	c.279+40114G>C		intron_variant		1		ENSP00000417557.1
FHIT	ENST00000468189.5	c.279+40114G>C		intron_variant		2		ENSP00000417480.1
FHIT	ENST00000466788.1	n.306+40114G>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58388 AN: 151774 Hom.: 13003 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.421

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

GnomAD4 genome AF: 0.385 AC: 58409 AN: 151892 Hom.: 13009 Cov.: 32 AF XY: 0.389 AC XY: 28836 AN XY: 74222

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.548

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.478

Gnomad4 FIN AF: 0.494

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.427

Alfa AF: 0.285 Hom.: 796

Bravo AF: 0.367

Asia WGS AF: 0.498 AC: 1730 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	9.3
DANN	Benign	0.56

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: rs6446101; hg19: chr3-59956983;