rs931317

Variant names:

• chr3-59943125-A-G
• rs931317
• NM_002012.4:c.280-20711T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002012.4(FHIT):​c.280-20711T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 148,708 control chromosomes in the GnomAD database, including 4,104 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 0.23 (4104 hom., cov: 31)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.280-20711T>C		intron_variant	Intron 7 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.280-20711T>C		intron_variant	Intron 7 of 9	1	NM_002012.4	ENSP00000418582.1
FHIT	ENST00000476844.5	c.280-20711T>C		intron_variant	Intron 7 of 9	1		ENSP00000417557.1
FHIT	ENST00000468189.5	c.280-20711T>C		intron_variant	Intron 7 of 8	2		ENSP00000417480.1
FHIT	ENST00000466788.1	n.307-20711T>C		intron_variant	Intron 4 of 6	4

Frequencies

GnomAD3 genomes AF: 0.231 AC: 34344 AN: 148582 Hom.: 4097 Cov.: 31

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.0161

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.240

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.231 AC: 34384 AN: 148708 Hom.: 4104 Cov.: 31 AF XY: 0.226 AC XY: 16449 AN XY: 72710

African (AFR) AF: 0.305 AC: 12318 AN: 40436

American (AMR) AF: 0.230 AC: 3445 AN: 14994

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1214 AN: 3418

East Asian (EAS) AF: 0.0161 AC: 79 AN: 4904

South Asian (SAS) AF: 0.215 AC: 1003 AN: 4670

European-Finnish (FIN) AF: 0.185 AC: 1940 AN: 10476

Middle Eastern (MID) AF: 0.229 AC: 66 AN: 288

European-Non Finnish (NFE) AF: 0.206 AC: 13736 AN: 66576

Other (OTH) AF: 0.222 AC: 457 AN: 2060

Alfa AF: 0.214 Hom.: 7388

Bravo AF: 0.237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.069
DANN	Benign	0.29
PhyloP100		-2.2
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: rs931317; hg19: chr3-59928851;