NM_002012.4:c.-18+123915C>T

Variant names:

• chr3-60698004-G-A
• rs1735457
• NM_002012.4:c.-18+123915C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002012.4(FHIT):​c.-18+123915C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 152,280 control chromosomes in the GnomAD database, including 65,283 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 0.93 (65283 hom., cov: 34)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• Publications: 2 publications found

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-18+123915C>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+123915C>T		intron_variant	Intron 4 of 9	1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140807 AN: 152162 Hom.: 65227 Cov.: 34

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.902

Gnomad FIN AF: 0.935

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.925

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

GnomAD4 genome AF: 0.925 AC: 140922 AN: 152280 Hom.: 65283 Cov.: 34 AF XY: 0.923 AC XY: 68702 AN XY: 74450

African (AFR) AF: 0.932 AC: 38767 AN: 41576

American (AMR) AF: 0.856 AC: 13090 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3107 AN: 3472

East Asian (EAS) AF: 0.883 AC: 4577 AN: 5186

South Asian (SAS) AF: 0.903 AC: 4360 AN: 4826

European-Finnish (FIN) AF: 0.935 AC: 9912 AN: 10604

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.941 AC: 63976 AN: 68010

Other (OTH) AF: 0.926 AC: 1956 AN: 2112

Alfa AF: 0.933 Hom.: 65792

Bravo AF: 0.920

Asia WGS AF: 0.886 AC: 3082 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.62
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1735457; hg19: chr3-60683737;