3-60137795-A-G

Variant names:

• chr3-60137795-A-G
• rs10510829
• NM_002012.4:c.104-123643T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	NM_002012.4	MANE Select	c.104-123643T>C		intron	N/A	NP_002003.1
	FHIT	NM_001166243.3		c.104-123643T>C		intron	N/A	NP_001159715.1
	FHIT	NM_001320899.2		c.104-123643T>C		intron	N/A	NP_001307828.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.104-123643T>C		intron	N/A	ENSP00000418582.1
	FHIT	ENST00000476844.5	TSL:1	c.104-123643T>C		intron	N/A	ENSP00000417557.1
	FHIT	ENST00000468189.5	TSL:2	c.104-123643T>C		intron	N/A	ENSP00000417480.1

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

African (AFR) AF: 0.0656 AC: 2728 AN: 41578

American (AMR) AF: 0.150 AC: 2293 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1085 AN: 3458

East Asian (EAS) AF: 0.131 AC: 681 AN: 5180

South Asian (SAS) AF: 0.283 AC: 1366 AN: 4820

European-Finnish (FIN) AF: 0.155 AC: 1643 AN: 10616

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15711 AN: 67968

Other (OTH) AF: 0.177 AC: 374 AN: 2114

Alfa AF: 0.216 Hom.: 12662

Bravo AF: 0.163

Asia WGS AF: 0.192 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.75
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10510829; hg19: chr3-60123522;