chr3-60803137-T-A

Variant names:

• chr3-60803137-T-A
• rs1447925
• NM_002012.4:c.-18+18782A>T

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-18+18782A>T		intron_variant	Intron 4 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.-18+18782A>T		intron_variant	Intron 4 of 9	1	NM_002012.4	ENSP00000418582.1

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

African (AFR) AF: 0.00586 AC: 243 AN: 41484

American (AMR) AF: 0.0116 AC: 178 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3468

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4808

European-Finnish (FIN) AF: 0.0155 AC: 164 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0335 AC: 2276 AN: 68006

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.000242 Hom.: 101431

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
PhyloP100		-0.066
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

dbSNP: rs1447925; hg19: chr3-60788842;