chr10-97319706-A-C

Position:

• chr10-97319706-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005479.4(FRAT1):​c.253A>C​(p.Lys85Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,028,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FRAT1 NM_005479.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.182

Genes affected

FRAT1 (HGNC:3944): (FRAT regulator of WNT signaling pathway 1) The protein encoded by this gene belongs to the GSK-3-binding protein family. The protein inhibits GSK-3-mediated phosphorylation of beta-catenin and positively regulates the Wnt signaling pathway. It may function in tumor progression and in lymphomagenesis. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13879019).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAT1	NM_005479.4	c.253A>C	p.Lys85Gln	missense_variant	1/1	ENST00000371021.5	NP_005470.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAT1	ENST00000371021.5	c.253A>C	p.Lys85Gln	missense_variant	1/1	6	NM_005479.4	ENSP00000360060.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000136 AC: 14 AN: 1028042 Hom.: 0 Cov.: 31 AF XY: 0.0000103 AC XY: 5 AN XY: 485352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.0000253

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 28, 2024

The c.253A>C (p.K85Q) alteration is located in exon 1 (coding exon 1) of the FRAT1 gene. This alteration results from a A to C substitution at nucleotide position 253, causing the lysine (K) at amino acid position 85 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.027
Sift	Benign	0.22	T
Sift4G	Benign	0.31	T
Polyphen		0.13	B
Vest4		0.044
MutPred		0.45		Loss of ubiquitination at K85 (P = 0.0051);
MVP		0.22
MPC		1.6
ClinPred		0.18	T
GERP RS		1.3
Varity_R		0.068
gMVP		0.096

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

LitVar

Other links and lift over

dbSNP: rs1843440751; hg19: chr10-99079463;