rs17679400

chr3-60746165-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002012.4(FHIT):c.-18+75754A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 152,220 control chromosomes in the GnomAD database, including 4,270 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 0.21 (4270 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.687

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.-18+75754A>G		intron_variant		ENST00000492590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.-18+75754A>G		intron_variant		1	NM_002012.4	P1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32145 AN: 152102 Hom.: 4273 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.211 AC: 32136 AN: 152220 Hom.: 4270 Cov.: 32 AF XY: 0.207 AC XY: 15371 AN XY: 74402

Gnomad4 AFR AF: 0.0547

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.260

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.227

Alfa AF: 0.279 Hom.: 5636

Bravo AF: 0.201

Asia WGS AF: 0.165 AC: 572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	14
Dann	Benign	0.75

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: rs17679400; hg19: chr3-60731898; COSMIC: COSV71807045;