rs3915504

chr3-60010140-T-G

Variant summary

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

The NM_002012.4(FHIT):c.279+1231A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 152,084 control chromosomes in the GnomAD database, including 27,213 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 0.60 (27213 hom., cov: 33)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.160

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 (SAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.279+1231A>C		intron_variant		ENST00000492590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.279+1231A>C		intron_variant		1	NM_002012.4	P1
FHIT	ENST00000476844.5	c.279+1231A>C		intron_variant		1		P1
FHIT	ENST00000468189.5	c.279+1231A>C		intron_variant		2		P1
FHIT	ENST00000466788.1	n.306+1231A>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90588 AN: 151966 Hom.: 27202 Cov.: 33

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.600

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

GnomAD4 genome AF: 0.596 AC: 90640 AN: 152084 Hom.: 27213 Cov.: 33 AF XY: 0.598 AC XY: 44450 AN XY: 74356

Gnomad4 AFR AF: 0.539

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.773

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.738

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.604

Alfa AF: 0.630 Hom.: 16115

Bravo AF: 0.580

Asia WGS AF: 0.580 AC: 2015 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	2.5
Dann	Benign	0.68

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: rs3915504; hg19: chr3-59995866;