3-61229823-G-T

Variant names:

• chr3-61229823-G-T
• rs10866046
• NM_002012.4:c.-213+21478C>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.-213+21478C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,010 control chromosomes in the GnomAD database, including 7,051 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 0.29 (7051 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.384
• Publications: 3 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-213+21478C>A		intron_variant	Intron 1 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.-213+21478C>A		intron_variant	Intron 1 of 9	1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43676 AN: 151892 Hom.: 7021 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.288 AC: 43748 AN: 152010 Hom.: 7051 Cov.: 32 AF XY: 0.297 AC XY: 22096 AN XY: 74298

African (AFR) AF: 0.198 AC: 8237 AN: 41516

American (AMR) AF: 0.414 AC: 6321 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 776 AN: 3464

East Asian (EAS) AF: 0.567 AC: 2919 AN: 5146

South Asian (SAS) AF: 0.493 AC: 2370 AN: 4810

European-Finnish (FIN) AF: 0.332 AC: 3499 AN: 10552

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.276 AC: 18746 AN: 67942

Other (OTH) AF: 0.289 AC: 611 AN: 2114

Alfa AF: 0.286 Hom.: 20360

Bravo AF: 0.291

Asia WGS AF: 0.519 AC: 1800 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.2
DANN	Benign	0.20
PhyloP100		0.38
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: rs10866046; hg19: chr3-61215497;