rs1447925

Positions:

• chr3-60803137-T-A
• chr3-60803137-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002012.4(FHIT):​c.-18+18782A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 152,118 control chromosomes in the GnomAD database, including 56 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 0.020 (56 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660

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=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0202 (3075/152118) while in subpopulation NFE AF= 0.0335 (2276/68006). AF 95% confidence interval is 0.0323. There are 56 homozygotes in gnomad4. There are 1431 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-18+18782A>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.-18+18782A>T		intron_variant		1	NM_002012.4	ENSP00000418582	P1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3073 AN: 152000 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00587

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0158

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

GnomAD4 genome AF: 0.0202 AC: 3075 AN: 152118 Hom.: 56 Cov.: 32 AF XY: 0.0192 AC XY: 1431 AN XY: 74362

Gnomad4 AFR AF: 0.00586

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.0335

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.000429 Hom.: 61809

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6

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: rs1447925; hg19: chr3-60788842;