chr3-59821052-G-A

Variant names:

• chr3-59821052-G-A
• rs1079196
• NM_002012.4:c.349-68731C>T

Variant summary

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

The NM_002012.4(FHIT):​c.349-68731C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,080 control chromosomes in the GnomAD database, including 4,039 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 0.22 (4039 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.178
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.349-68731C>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.349-68731C>T		intron_variant	Intron 8 of 9	1	NM_002012.4	ENSP00000418582.1
FHIT	ENST00000476844.5	c.349-68731C>T		intron_variant	Intron 8 of 9	1		ENSP00000417557.1
FHIT	ENST00000468189.5	c.349-68731C>T		intron_variant	Intron 8 of 8	2		ENSP00000417480.1
FHIT	ENST00000466788.1	n.443+65168C>T		intron_variant	Intron 6 of 6	4

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33360 AN: 151962 Hom.: 4032 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.215

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

GnomAD4 genome AF: 0.220 AC: 33400 AN: 152080 Hom.: 4039 Cov.: 32 AF XY: 0.214 AC XY: 15925 AN XY: 74356

African (AFR) AF: 0.320 AC: 13272 AN: 41428

American (AMR) AF: 0.161 AC: 2457 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 839 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5188

South Asian (SAS) AF: 0.129 AC: 620 AN: 4822

European-Finnish (FIN) AF: 0.159 AC: 1684 AN: 10576

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13780 AN: 68002

Other (OTH) AF: 0.213 AC: 448 AN: 2108

Alfa AF: 0.206 Hom.: 3177

Bravo AF: 0.226

Asia WGS AF: 0.0790 AC: 274 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.78
PhyloP100		-0.18
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: rs1079196; hg19: chr3-59806778;