3-59825141-C-T

Variant names:

• chr3-59825141-C-T
• rs4679614
• NM_002012.4:c.349-72820G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002012.4(FHIT):​c.349-72820G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 152,138 control chromosomes in the GnomAD database, including 41,907 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 0.72 (41907 hom., cov: 33)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.816
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.349-72820G>A		intron_variant	Intron 8 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.349-72820G>A		intron_variant	Intron 8 of 9	1	NM_002012.4	ENSP00000418582.1
FHIT	ENST00000476844.5	c.349-72820G>A		intron_variant	Intron 8 of 9	1		ENSP00000417557.1
FHIT	ENST00000468189.5	c.349-72820G>A		intron_variant	Intron 8 of 8	2		ENSP00000417480.1
FHIT	ENST00000466788.1	n.443+61079G>A		intron_variant	Intron 6 of 6	4

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110117 AN: 152020 Hom.: 41895 Cov.: 33

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.848

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.738

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

GnomAD4 genome AF: 0.724 AC: 110155 AN: 152138 Hom.: 41907 Cov.: 33 AF XY: 0.732 AC XY: 54421 AN XY: 74380

African (AFR) AF: 0.465 AC: 19297 AN: 41472

American (AMR) AF: 0.814 AC: 12439 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 2613 AN: 3472

East Asian (EAS) AF: 0.967 AC: 4999 AN: 5172

South Asian (SAS) AF: 0.887 AC: 4279 AN: 4824

European-Finnish (FIN) AF: 0.848 AC: 8988 AN: 10602

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.809 AC: 55035 AN: 68002

Other (OTH) AF: 0.740 AC: 1562 AN: 2110

Alfa AF: 0.794 Hom.: 138152

Bravo AF: 0.711

Asia WGS AF: 0.896 AC: 3115 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.63
PhyloP100		0.82
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: rs4679614; hg19: chr3-59810867;