3-60912762-T-C

Variant names:

• chr3-60912762-T-C
• rs11130795
• NM_002012.4:c.-110-90751A>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.-110-90751A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 514,662 control chromosomes in the GnomAD database, including 49,513 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 0.35 (11558 hom., cov: 32)
  • Exomes 𝑓: 0.44 (37955 hom.)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 6 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 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.-110-90751A>G		intron	N/A	NP_002003.1
	FHIT	NM_001166243.3		c.-110-90751A>G		intron	N/A	NP_001159715.1
	FHIT	NM_001320899.2		c.-110-90751A>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.-110-90751A>G		intron	N/A	ENSP00000418582.1
	FHIT	ENST00000476844.5	TSL:1	c.-110-90751A>G		intron	N/A	ENSP00000417557.1
	FHIT	ENST00000490952.1	TSL:1	n.458-90751A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53115 AN: 151984 Hom.: 11554 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.446 AC: 100817 AN: 225798 AF XY: 0.442

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.834

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.437 AC: 158498 AN: 362560 Hom.: 37955 Cov.: 0 AF XY: 0.436 AC XY: 90705 AN XY: 207920

African (AFR) AF: 0.114 AC: 1192 AN: 10438

American (AMR) AF: 0.591 AC: 20952 AN: 35428

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 2773 AN: 11666

East Asian (EAS) AF: 0.838 AC: 10936 AN: 13052

South Asian (SAS) AF: 0.470 AC: 30765 AN: 65454

European-Finnish (FIN) AF: 0.443 AC: 7449 AN: 16830

Middle Eastern (MID) AF: 0.264 AC: 751 AN: 2842

European-Non Finnish (NFE) AF: 0.405 AC: 77105 AN: 190372

Other (OTH) AF: 0.399 AC: 6575 AN: 16478

GnomAD4 genome AF: 0.349 AC: 53138 AN: 152102 Hom.: 11558 Cov.: 32 AF XY: 0.359 AC XY: 26695 AN XY: 74362

African (AFR) AF: 0.122 AC: 5046 AN: 41524

American (AMR) AF: 0.463 AC: 7072 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3470

East Asian (EAS) AF: 0.833 AC: 4305 AN: 5168

South Asian (SAS) AF: 0.489 AC: 2359 AN: 4820

European-Finnish (FIN) AF: 0.452 AC: 4779 AN: 10578

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27727 AN: 67950

Other (OTH) AF: 0.322 AC: 678 AN: 2108

Alfa AF: 0.372 Hom.: 2753

Bravo AF: 0.340

Asia WGS AF: 0.588 AC: 2041 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.1
DANN	Benign	0.79
PhyloP100		-0.082
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: rs11130795; hg19: chr3-60898434;