3-59752240-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002012.4(FHIT):c.430G>A(p.Val144Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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)
• Consequence: FHIT NM_002012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.471

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12785983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHIT	NM_002012.4	c.430G>A	p.Val144Ile	missense_variant	9/10	ENST00000492590.6
CFAP20DC-DT	XR_002959675.2	n.1218-57492C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHIT	ENST00000492590.6	c.430G>A	p.Val144Ile	missense_variant	9/10	1	NM_002012.4	P1
CFAP20DC-DT	ENST00000668131.1	n.678-2153C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.430G>A (p.V144I) alteration is located in exon 9 (coding exon 5) of the FHIT gene. This alteration results from a G to A substitution at nucleotide position 430, causing the valine (V) at amino acid position 144 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.069	N
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.073	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.14
MutPred		0.35		Loss of methylation at R143 (P = 0.0584);Loss of methylation at R143 (P = 0.0584);Loss of methylation at R143 (P = 0.0584);
MVP		0.17
MPC		0.013
ClinPred		0.10	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.066

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-59737966;