3-60137795-A-G

Position:

• chr3-60137795-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002012.4(FHIT):​c.104-123643T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,230 control chromosomes in the GnomAD database, including 2,794 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 0.17 (2794 hom., cov: 33)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.304

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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.104-123643T>C		intron_variant		ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.104-123643T>C		intron_variant		1	NM_002012.4	ENSP00000418582.1
FHIT	ENST00000476844.5	c.104-123643T>C		intron_variant		1		ENSP00000417557.1
FHIT	ENST00000468189.5	c.104-123643T>C		intron_variant		2		ENSP00000417480.1
FHIT	ENST00000488467.5	c.104-123643T>C		intron_variant		3		ENSP00000418596.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26116 AN: 152112 Hom.: 2791 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.178

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

GnomAD4 genome AF: 0.172 AC: 26130 AN: 152230 Hom.: 2794 Cov.: 33 AF XY: 0.172 AC XY: 12807 AN XY: 74430

Gnomad4 AFR AF: 0.0656

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.177

Alfa AF: 0.228 Hom.: 8965

Bravo AF: 0.163

Asia WGS AF: 0.192 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs10510829; hg19: chr3-60123522;