rs9874888

Positions:

• chr3-60030591-T-A
• chr3-60030591-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.104-16439A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,072 control chromosomes in the GnomAD database, including 6,996 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 0.30 (6996 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236

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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.104-16439A>T		intron_variant		ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.104-16439A>T		intron_variant		1	NM_002012.4	ENSP00000418582	P1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45454 AN: 151954 Hom.: 6993 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.274

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

GnomAD4 genome AF: 0.299 AC: 45493 AN: 152072 Hom.: 6996 Cov.: 32 AF XY: 0.302 AC XY: 22466 AN XY: 74334

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.277

Alfa AF: 0.300 Hom.: 854

Bravo AF: 0.298

Asia WGS AF: 0.406 AC: 1410 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.80
DANN	Benign	0.72

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: rs9874888; hg19: chr3-60016317;