rs9311745

chr3-60016099-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_002012.4(FHIT):c.104-1947A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,214 control chromosomes in the GnomAD database, including 1,303 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 0.11 (1303 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.104-1947A>G		intron_variant		ENST00000492590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.104-1947A>G		intron_variant		1	NM_002012.4	P1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16216 AN: 152096 Hom.: 1297 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0503

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.107 AC: 16249 AN: 152214 Hom.: 1303 Cov.: 32 AF XY: 0.110 AC XY: 8195 AN XY: 74438

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.0384

Gnomad4 NFE AF: 0.0503

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0667 Hom.: 845

Bravo AF: 0.118

Asia WGS AF: 0.226 AC: 782 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	19
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9311745; hg19: chr3-60001825;