rs3845972

Positions:

• chr3-60042108-G-A
• chr3-60042108-G-C

Variant summary

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

The NM_002012.4(FHIT):​c.104-27956C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 152,016 control chromosomes in the GnomAD database, including 24,613 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 0.56 (24613 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0340

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.104-27956C>T		intron_variant		ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.104-27956C>T		intron_variant		1	NM_002012.4	ENSP00000418582	P1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85298 AN: 151898 Hom.: 24589 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.760

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.590

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

GnomAD4 genome AF: 0.562 AC: 85361 AN: 152016 Hom.: 24613 Cov.: 32 AF XY: 0.557 AC XY: 41365 AN XY: 74294

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.608

Gnomad4 NFE AF: 0.639

Gnomad4 OTH AF: 0.584

Alfa AF: 0.584 Hom.: 12105

Bravo AF: 0.551

Asia WGS AF: 0.358 AC: 1243 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs3845972; hg19: chr3-60027834;