rs1447971

Positions:

• chr3-60479546-G-A
• chr3-60479546-G-C
• chr3-60479546-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.103+57314C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 152,070 control chromosomes in the GnomAD database, including 17,486 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 0.45 (17486 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.103+57314C>T		intron_variant		ENST00000492590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.103+57314C>T		intron_variant		1	NM_002012.4	P1
FHIT	ENST00000476844.5	c.103+57314C>T		intron_variant		1		P1
FHIT	ENST00000468189.5	c.103+57314C>T		intron_variant		2		P1
FHIT	ENST00000488467.5	c.103+57314C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68992 AN: 151952 Hom.: 17436 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.481

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

GnomAD4 genome AF: 0.454 AC: 69100 AN: 152070 Hom.: 17486 Cov.: 32 AF XY: 0.452 AC XY: 33641 AN XY: 74358

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.505

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.548

Gnomad4 SAS AF: 0.577

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.484

Alfa AF: 0.379 Hom.: 15975

Bravo AF: 0.483

Asia WGS AF: 0.583 AC: 2021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.34
DANN	Benign	0.24

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: rs1447971; hg19: chr3-60465279;