rs1735457

Positions:

• chr3-60698004-G-A
• chr3-60698004-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002012.4(FHIT):​c.-18+123915C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 152,280 control chromosomes in the GnomAD database, including 65,283 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 0.93 (65283 hom., cov: 34)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-18+123915C>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.-18+123915C>T		intron_variant		1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140807 AN: 152162 Hom.: 65227 Cov.: 34

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.902

Gnomad FIN AF: 0.935

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.925

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

GnomAD4 genome AF: 0.925 AC: 140922 AN: 152280 Hom.: 65283 Cov.: 34 AF XY: 0.923 AC XY: 68702 AN XY: 74450

Gnomad4 AFR AF: 0.932

Gnomad4 AMR AF: 0.856

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.883

Gnomad4 SAS AF: 0.903

Gnomad4 FIN AF: 0.935

Gnomad4 NFE AF: 0.941

Gnomad4 OTH AF: 0.926

Alfa AF: 0.936 Hom.: 46382

Bravo AF: 0.920

Asia WGS AF: 0.886 AC: 3082 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.62

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: rs1735457; hg19: chr3-60683737;