3-59995799-T-C

Position:

• chr3-59995799-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002012.4(FHIT):​c.279+15572A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,878 control chromosomes in the GnomAD database, including 9,120 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 0.33 (9120 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651

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]

FHIT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.279+15572A>G		intron_variant		ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.279+15572A>G		intron_variant		1	NM_002012.4	ENSP00000418582.1
FHIT	ENST00000476844.5	c.279+15572A>G		intron_variant		1		ENSP00000417557.1
FHIT	ENST00000468189.5	c.279+15572A>G		intron_variant		2		ENSP00000417480.1
FHIT	ENST00000466788.1	n.306+15572A>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50678 AN: 151758 Hom.: 9111 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.298

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

GnomAD4 genome AF: 0.334 AC: 50734 AN: 151878 Hom.: 9120 Cov.: 32 AF XY: 0.339 AC XY: 25141 AN XY: 74190

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.294

Alfa AF: 0.263 Hom.: 12338

Bravo AF: 0.340

Asia WGS AF: 0.416 AC: 1446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.81
DANN	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs212016; hg19: chr3-59981525;