3-60210809-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.104-196657C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 151,966 control chromosomes in the GnomAD database, including 1,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (★).

• Frequency: Genomes: 𝑓 0.12 (1043 hom., cov: 31)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: association criteria provided, single submitter O:1
• Conservation: PhyloP100: 1.06

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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.104-196657C>A		intron_variant		ENST00000492590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.104-196657C>A		intron_variant		1	NM_002012.4	P1
FHIT	ENST00000476844.5	c.104-196657C>A		intron_variant		1		P1
FHIT	ENST00000468189.5	c.104-196657C>A		intron_variant		2		P1
FHIT	ENST00000488467.5	c.104-196657C>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17486 AN: 151848 Hom.: 1042 Cov.: 31

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.0609

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0973

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

GnomAD4 genome AF: 0.115 AC: 17492 AN: 151966 Hom.: 1043 Cov.: 31 AF XY: 0.118 AC XY: 8722 AN XY: 74224

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0964

Gnomad4 ASJ AF: 0.0609

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.0958

Alfa AF: 0.0997 Hom.: 1117

Bravo AF: 0.114

Asia WGS AF: 0.136 AC: 474 AN: 3476

ClinVar

Significance: association

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lip and oral cavity carcinoma Other:1

association, criteria provided, single submitter

case-control

Department of Biological Science, Sunandan Divatia School of Science, NMIMS University

Jan 01, 2016

A significant association of rs11130760 (FHIT) GG (odds ratio [OR] 1.41; 95% confidence interval [CI] 1.08-1.84) indicated increased risk. The SNP rs11130760 (FHIT) wild-type (WT) allele G indicated an increased risk for oral cancer (OR 1.38; 95% CI 1.09-1.73), whereas SNP allele T indicated a decreased risk (OR 0.73; 95% CI 0.58-0.92) for oral cancer. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	4.7
Dann	Benign	0.22

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: rs11130760; hg19: chr3-60196537;