chr3-59995799-T-C

Variant names:

• chr3-59995799-T-C
• rs212016
• NM_002012.4:c.279+15572A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002012.4(FHIT):​c.279+15572A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,878 control chromosomes in the GnomAD database, including 9,120 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 0.33 (9120 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651
• Publications: 8 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	NM_002012.4	MANE Select	c.279+15572A>G		intron	N/A	NP_002003.1
	FHIT	NM_001166243.3		c.279+15572A>G		intron	N/A	NP_001159715.1
	FHIT	NM_001320899.2		c.279+15572A>G		intron	N/A	NP_001307828.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.279+15572A>G		intron	N/A	ENSP00000418582.1
	FHIT	ENST00000476844.5	TSL:1	c.279+15572A>G		intron	N/A	ENSP00000417557.1
	FHIT	ENST00000468189.5	TSL:2	c.279+15572A>G		intron	N/A	ENSP00000417480.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50678 AN: 151758 Hom.: 9111 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.298

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

GnomAD4 genome AF: 0.334 AC: 50734 AN: 151878 Hom.: 9120 Cov.: 32 AF XY: 0.339 AC XY: 25141 AN XY: 74190

African (AFR) AF: 0.464 AC: 19231 AN: 41428

American (AMR) AF: 0.343 AC: 5232 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 736 AN: 3468

East Asian (EAS) AF: 0.380 AC: 1941 AN: 5106

South Asian (SAS) AF: 0.430 AC: 2068 AN: 4808

European-Finnish (FIN) AF: 0.291 AC: 3081 AN: 10574

Middle Eastern (MID) AF: 0.248 AC: 72 AN: 290

European-Non Finnish (NFE) AF: 0.258 AC: 17560 AN: 67942

Other (OTH) AF: 0.294 AC: 621 AN: 2112

Alfa AF: 0.280 Hom.: 22104

Bravo AF: 0.340

Asia WGS AF: 0.416 AC: 1446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.81
DANN	Benign	0.26
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs212016; hg19: chr3-59981525;