chr3-60210809-G-T

Variant names:

• chr3-60210809-G-T
• rs11130760
• NM_002012.4:c.104-196657C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	NM_002012.4	MANE Select	c.104-196657C>A		intron	N/A	NP_002003.1	P49789
	FHIT	NM_001166243.3		c.104-196657C>A		intron	N/A	NP_001159715.1	P49789
	FHIT	NM_001320899.2		c.104-196657C>A		intron	N/A	NP_001307828.1	P49789

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.104-196657C>A		intron	N/A	ENSP00000418582.1	P49789
	FHIT	ENST00000476844.5	TSL:1	c.104-196657C>A		intron	N/A	ENSP00000417557.1	P49789
	FHIT	ENST00000468189.5	TSL:2	c.104-196657C>A		intron	N/A	ENSP00000417480.1	P49789

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

African (AFR) AF: 0.133 AC: 5529 AN: 41476

American (AMR) AF: 0.0964 AC: 1471 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0609 AC: 210 AN: 3450

East Asian (EAS) AF: 0.127 AC: 656 AN: 5166

South Asian (SAS) AF: 0.142 AC: 681 AN: 4808

European-Finnish (FIN) AF: 0.136 AC: 1432 AN: 10542

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7163 AN: 67956

Other (OTH) AF: 0.0958 AC: 202 AN: 2108

Alfa AF: 0.102 Hom.: 1576

Bravo AF: 0.114

Asia WGS AF: 0.136 AC: 474 AN: 3476

ClinVar

ClinVar submissions

Significance: association

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	-	Lip and oral cavity carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.7
DANN	Benign	0.22
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11130760; hg19: chr3-60196537;