rs10428174

Variant names:

• chr3-59828322-G-A
• rs10428174
• NM_002012.4:c.349-76001C>T

Variant summary

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

The NM_002012.4(FHIT):​c.349-76001C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 152,108 control chromosomes in the GnomAD database, including 41,171 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 0.73 (41171 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.241

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=-0.38).
• 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.349-76001C>T		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.349-76001C>T		intron_variant	Intron 8 of 9	1	NM_002012.4	ENSP00000418582.1
FHIT	ENST00000476844.5	c.349-76001C>T		intron_variant	Intron 8 of 9	1		ENSP00000417557.1
FHIT	ENST00000468189.5	c.349-76001C>T		intron_variant	Intron 8 of 8	2		ENSP00000417480.1
FHIT	ENST00000466788.1	n.443+57898C>T		intron_variant	Intron 6 of 6	4

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110551 AN: 151990 Hom.: 41153 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.730

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

GnomAD4 genome AF: 0.727 AC: 110614 AN: 152108 Hom.: 41171 Cov.: 32 AF XY: 0.733 AC XY: 54535 AN XY: 74352

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.810

Gnomad4 ASJ AF: 0.719

Gnomad4 EAS AF: 0.967

Gnomad4 SAS AF: 0.849

Gnomad4 FIN AF: 0.813

Gnomad4 NFE AF: 0.776

Gnomad4 OTH AF: 0.734

Alfa AF: 0.768 Hom.: 29989

Bravo AF: 0.720

Asia WGS AF: 0.880 AC: 3055 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.69

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: rs10428174; hg19: chr3-59814048;