3-60536957-C-A

Position:

• chr3-60536957-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002012.4(FHIT):​c.6G>T​(p.Ser2Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,608,544 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. S2S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (58 hom.)
• Consequence: FHIT NM_002012.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 3-60536957-C-A is Benign according to our data. Variant chr3-60536957-C-A is described in ClinVar as [Benign]. Clinvar id is 708320.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-60536957-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIT	NM_002012.4	c.6G>T	p.Ser2Ser	synonymous_variant	5/10	ENST00000492590.6	NP_002003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIT	ENST00000492590.6	c.6G>T	p.Ser2Ser	synonymous_variant	5/10	1	NM_002012.4	ENSP00000418582.1

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 691 AN: 151884 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00561 AC: 1387 AN: 247094 Hom.: 21 AF XY: 0.00558 AC XY: 745 AN XY: 133418

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.000834

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000375

Gnomad FIN exome AF: 0.0379

Gnomad NFE exome AF: 0.00425

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00390 AC: 5680 AN: 1456550 Hom.: 58 Cov.: 32 AF XY: 0.00382 AC XY: 2764 AN XY: 724390

Gnomad4 AFR exome AF: 0.000481

Gnomad4 AMR exome AF: 0.000934

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000459

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.00295

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00455 AC: 691 AN: 151994 Hom.: 14 Cov.: 32 AF XY: 0.00601 AC XY: 446 AN XY: 74260

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00317 Hom.: 0

Bravo AF: 0.00174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.039
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137953369; hg19: chr3-60522690;