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GeneBe

3-60536957-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_002012.4(FHIT):c.6G>T(p.Ser2=) 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

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.70
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.7 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FHITNM_002012.4 linkuse as main transcriptc.6G>T p.Ser2= synonymous_variant 5/10 ENST00000492590.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FHITENST00000492590.6 linkuse as main transcriptc.6G>T p.Ser2= synonymous_variant 5/101 NM_002012.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00455
AC:
691
AN:
151884
Hom.:
14
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00455
AC:
691
AN:
151994
Hom.:
14
Cov.:
32
AF XY:
0.00601
AC XY:
446
AN XY:
74260
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeAug 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137953369; hg19: chr3-60522690; API