rs6800603

chr3-60215651-A-G

Variant summary

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

The NM_002012.4(FHIT):c.104-201499T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 152,320 control chromosomes in the GnomAD database, including 198 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 0.029 (198 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.206

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.104-201499T>C		intron_variant		ENST00000492590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.104-201499T>C		intron_variant		1	NM_002012.4	P1
FHIT	ENST00000476844.5	c.104-201499T>C		intron_variant		1		P1
FHIT	ENST00000468189.5	c.104-201499T>C		intron_variant		2		P1
FHIT	ENST00000488467.5	c.104-201499T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4417 AN: 152202 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0935

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.00723

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.0282

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

GnomAD4 genome AF: 0.0291 AC: 4437 AN: 152320 Hom.: 198 Cov.: 32 AF XY: 0.0277 AC XY: 2066 AN XY: 74492

Gnomad4 AFR AF: 0.0938

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.00723

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00284

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0206 Hom.: 20

Bravo AF: 0.0336

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.94
Dann	Benign	0.48

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: rs6800603; hg19: chr3-60201379;