3-59825911-A-G

Position:

• chr3-59825911-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.349-73590T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 152,056 control chromosomes in the GnomAD database, including 42,535 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 0.73 (42535 hom., cov: 31)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.349-73590T>C		intron_variant		ENST00000492590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.349-73590T>C		intron_variant		1	NM_002012.4	P1
FHIT	ENST00000476844.5	c.349-73590T>C		intron_variant		1		P1
FHIT	ENST00000468189.5	c.349-73590T>C		intron_variant		2		P1
FHIT	ENST00000466788.1	n.443+60309T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.731 AC: 111138 AN: 151938 Hom.: 42521 Cov.: 31

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.744

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

GnomAD4 genome AF: 0.731 AC: 111184 AN: 152056 Hom.: 42535 Cov.: 31 AF XY: 0.739 AC XY: 54951 AN XY: 74350

Gnomad4 AFR AF: 0.482

Gnomad4 AMR AF: 0.817

Gnomad4 ASJ AF: 0.775

Gnomad4 EAS AF: 0.967

Gnomad4 SAS AF: 0.888

Gnomad4 FIN AF: 0.858

Gnomad4 NFE AF: 0.812

Gnomad4 OTH AF: 0.746

Alfa AF: 0.757 Hom.: 5271

Bravo AF: 0.718

Asia WGS AF: 0.903 AC: 3141 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.11
DANN	Benign	0.75

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: rs1872495; hg19: chr3-59811637;