NM_002012.4:c.421G>T

Variant names:

• chr3-59752249-C-A
• rs200185369
• NM_002012.4:c.421G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002012.4(FHIT):​c.421G>T​(p.Ala141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: FHIT NM_002012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 3 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]

CFAP20DC-DT (HGNC:55618): (CFAP20DC divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13492).

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.421G>T	p.Ala141Ser	missense	Exon 9 of 10	NP_002003.1	P49789
	FHIT	NM_001166243.3		c.421G>T	p.Ala141Ser	missense	Exon 9 of 10	NP_001159715.1	P49789
	FHIT	NM_001320899.2		c.421G>T	p.Ala141Ser	missense	Exon 9 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.421G>T	p.Ala141Ser	missense	Exon 9 of 10	ENSP00000418582.1	P49789
	FHIT	ENST00000476844.5	TSL:1	c.421G>T	p.Ala141Ser	missense	Exon 9 of 10	ENSP00000417557.1	P49789
	FHIT	ENST00000468189.5	TSL:2	c.421G>T	p.Ala141Ser	missense	Exon 9 of 9	ENSP00000417480.1	P49789

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000360 AC: 9 AN: 250202 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: 0.0000708

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460674 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20 AN XY: 726642

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111220

Other (OTH) AF: 0.0000166 AC: 1 AN: 60336

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000796 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

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	0.085
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.9
DANN	Benign	0.61
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.16
Sift	Benign	0.57	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.18
MVP		0.14
MPC		0.013
ClinPred		0.053	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.11
Mutation Taster		=72/28	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: rs200185369; hg19: chr3-59737975; COSMIC: COSV59324323;