chr3-60777523-G-T

Variant names:

• chr3-60777523-G-T
• rs11919041
• NM_002012.4:c.-18+44396C>A

Variant summary

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

The NM_002012.4(FHIT):​c.-18+44396C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,008 control chromosomes in the GnomAD database, including 8,154 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 0.31 (8154 hom., cov: 32)
• Consequence: FHIT NM_002012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHIT	NM_002012.4	c.-18+44396C>A		intron_variant	Intron 4 of 9	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.-18+44396C>A		intron_variant	Intron 4 of 9	1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47648 AN: 151890 Hom.: 8141 Cov.: 32

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.0967

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.314 AC: 47698 AN: 152008 Hom.: 8154 Cov.: 32 AF XY: 0.314 AC XY: 23355 AN XY: 74318

African (AFR) AF: 0.421 AC: 17437 AN: 41414

American (AMR) AF: 0.236 AC: 3605 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1189 AN: 3468

East Asian (EAS) AF: 0.0973 AC: 502 AN: 5158

South Asian (SAS) AF: 0.148 AC: 715 AN: 4822

European-Finnish (FIN) AF: 0.374 AC: 3956 AN: 10574

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19188 AN: 67970

Other (OTH) AF: 0.323 AC: 681 AN: 2108

Alfa AF: 0.0662 Hom.: 362

Bravo AF: 0.308

Asia WGS AF: 0.173 AC: 602 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	4.5
DANN	Benign	0.59
PhyloP100		0.34
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: rs11919041; hg19: chr3-60763256;