chr3-60089466-T-C

Variant names:

• chr3-60089466-T-C
• rs1040336
• NM_002012.4:c.104-75314A>G

Variant summary

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

The NM_002012.4(FHIT):​c.104-75314A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 151,890 control chromosomes in the GnomAD database, including 4,004 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 0.21 (4004 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 2 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]

ENSG00000299680 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.104-75314A>G		intron_variant	Intron 5 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.104-75314A>G		intron_variant	Intron 5 of 9	1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31965 AN: 151772 Hom.: 3989 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.211 AC: 32022 AN: 151890 Hom.: 4004 Cov.: 32 AF XY: 0.217 AC XY: 16108 AN XY: 74228

African (AFR) AF: 0.212 AC: 8803 AN: 41430

American (AMR) AF: 0.293 AC: 4469 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3462

East Asian (EAS) AF: 0.514 AC: 2644 AN: 5148

South Asian (SAS) AF: 0.243 AC: 1171 AN: 4816

European-Finnish (FIN) AF: 0.252 AC: 2657 AN: 10530

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

European-Non Finnish (NFE) AF: 0.165 AC: 11216 AN: 67938

Other (OTH) AF: 0.210 AC: 443 AN: 2108

Alfa AF: 0.181 Hom.: 11882

Bravo AF: 0.215

Asia WGS AF: 0.394 AC: 1370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.7
DANN	Benign	0.58
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: rs1040336; hg19: chr3-60075192;