rs746933635

Variant names:

• chr3-60014014-G-C
• rs746933635
• NM_002012.4:c.242C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-60014014-G-C
• chr3-60014014-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_002012.4(FHIT):​c.242C>G​(p.Ser81Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: FHIT NM_002012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.07
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3352142).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	NM_002012.4	MANE Select	c.242C>G	p.Ser81Cys	missense	Exon 6 of 10	NP_002003.1	P49789
	FHIT	NM_001166243.3		c.242C>G	p.Ser81Cys	missense	Exon 6 of 10	NP_001159715.1	P49789
	FHIT	NM_001320899.2		c.242C>G	p.Ser81Cys	missense	Exon 6 of 9	NP_001307828.1	P49789

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHIT	ENST00000492590.6	TSL:1 MANE Select	c.242C>G	p.Ser81Cys	missense	Exon 6 of 10	ENSP00000418582.1	P49789
	FHIT	ENST00000476844.5	TSL:1	c.242C>G	p.Ser81Cys	missense	Exon 6 of 10	ENSP00000417557.1	P49789
	FHIT	ENST00000468189.5	TSL:2	c.242C>G	p.Ser81Cys	missense	Exon 6 of 9	ENSP00000417480.1	P49789

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250602 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111812

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.77	N
PhyloP100		5.1
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.27
Sift	Benign	0.091	T
Sift4G	Benign	0.078	T
Polyphen		0.0010	B
Vest4		0.48
MutPred		0.50		Loss of disorder (P = 0.0084)
MVP		0.89
MPC		0.014
ClinPred		0.12	T
GERP RS		4.9
PromoterAI		-0.0048	Neutral
Varity_R		0.38
gMVP		0.48
Mutation Taster		=52/48	polymorphism

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: rs746933635; hg19: chr3-59999740;