3-61141532-T-C

Variant names:

• chr3-61141532-T-C
• rs9877396
• NM_002012.4:c.-164+59085A>G

Variant summary

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

The NM_002012.4(FHIT):​c.-164+59085A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 145,882 control chromosomes in the GnomAD database, including 5,812 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 0.26 (5812 hom., cov: 31)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-164+59085A>G		intron_variant	Intron 2 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.-164+59085A>G		intron_variant	Intron 2 of 9	1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 38212 AN: 145752 Hom.: 5818 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.222

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

GnomAD4 genome AF: 0.262 AC: 38233 AN: 145882 Hom.: 5812 Cov.: 31 AF XY: 0.267 AC XY: 19068 AN XY: 71358

African (AFR) AF: 0.223 AC: 9160 AN: 41032

American (AMR) AF: 0.352 AC: 5143 AN: 14598

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 375 AN: 3130

East Asian (EAS) AF: 0.446 AC: 2292 AN: 5134

South Asian (SAS) AF: 0.256 AC: 1198 AN: 4676

European-Finnish (FIN) AF: 0.311 AC: 3138 AN: 10076

Middle Eastern (MID) AF: 0.117 AC: 33 AN: 282

European-Non Finnish (NFE) AF: 0.255 AC: 16339 AN: 64074

Other (OTH) AF: 0.221 AC: 440 AN: 1990

Alfa AF: 0.239 Hom.: 10377

Bravo AF: 0.255

Asia WGS AF: 0.324 AC: 1125 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.1
DANN	Benign	0.57
PhyloP100		0.035
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: rs9877396; hg19: chr3-61127205;