3-59825911-A-G

Variant names:

• chr3-59825911-A-G
• rs1872495
• NM_002012.4:c.349-73590T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	NM_002012.4	MANE Select	c.349-73590T>C		intron	N/A	NP_002003.1	P49789
	FHIT	NM_001166243.3		c.349-73590T>C		intron	N/A	NP_001159715.1	P49789
	FHIT	NM_001320899.2		c.349-73590T>C		intron	N/A	NP_001307828.1	P49789

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.349-73590T>C		intron	N/A	ENSP00000418582.1	P49789
	FHIT	ENST00000476844.5	TSL:1	c.349-73590T>C		intron	N/A	ENSP00000417557.1	P49789
	FHIT	ENST00000468189.5	TSL:2	c.349-73590T>C		intron	N/A	ENSP00000417480.1	P49789

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

African (AFR) AF: 0.482 AC: 19960 AN: 41418

American (AMR) AF: 0.817 AC: 12474 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2685 AN: 3466

East Asian (EAS) AF: 0.967 AC: 4998 AN: 5170

South Asian (SAS) AF: 0.888 AC: 4277 AN: 4816

European-Finnish (FIN) AF: 0.858 AC: 9082 AN: 10590

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55185 AN: 68000

Other (OTH) AF: 0.746 AC: 1578 AN: 2114

Alfa AF: 0.801 Hom.: 58934

Bravo AF: 0.718

Asia WGS AF: 0.903 AC: 3141 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.11
DANN	Benign	0.75
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1872495; hg19: chr3-59811637;