10-48163542-G-A

Variant names:

• chr10-48163542-G-A
• NM_001018071.4:c.3667C>T

Variant summary

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

The NM_001018071.4(FRMPD2):​c.3667C>T​(p.Leu1223Phe) 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. 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: 28)
• Consequence: FRMPD2 NM_001018071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

FRMPD2 (HGNC:28572): (FERM and PDZ domain containing 2) This gene encodes a peripheral membrane protein and is located in a region of chromosome 10q that contains a segmental duplication. This copy of the gene is full-length and is in the telomeric duplicated region. Two other more centromerically proximal copies of the gene are partial and may represent pseudogenes. This full-length gene appears to function in the establishment and maintenance of cell polarization. The protein is recruited to cell-cell junctions in an E-cadherin-dependent manner, and is selectively localized at the basolateral membrane in polarized epithelial cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2009]

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=0.14321181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4	c.3667C>T	p.Leu1223Phe	missense_variant	Exon 28 of 29	ENST00000374201.8	NP_001018081.4
FRMPD2	NM_001318191.1	c.3592C>T	p.Leu1198Phe	missense_variant	Exon 26 of 27		NP_001305120.1
FRMPD2	NM_001042512.3	c.700C>T	p.Leu234Phe	missense_variant	Exon 5 of 6		NP_001035977.3
FRMPD2	XM_017015744.2	c.523C>T	p.Leu175Phe	missense_variant	Exon 5 of 6		XP_016871233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMPD2	ENST00000374201.8	c.3667C>T	p.Leu1223Phe	missense_variant	Exon 28 of 29	1	NM_001018071.4	ENSP00000363317.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 15

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3667C>T (p.L1223F) alteration is located in exon 28 (coding exon 28) of the FRMPD2 gene. This alteration results from a C to T substitution at nucleotide position 3667, causing the leucine (L) at amino acid position 1223 to be replaced by a phenylalanine (F). 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	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	.;L;.
PhyloP100		1.1
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.2	.;N;N
REVEL	Benign	0.082
Sift	Benign	0.089	.;T;T
Sift4G	Benign	0.092	.;T;T
Polyphen		0.98, 0.96	.;D;D
Vest4		0.096, 0.067
MutPred		0.21		Loss of MoRF binding (P = 0.2028);Loss of MoRF binding (P = 0.2028);.;
MVP		0.58
MPC		2.5
ClinPred		0.55	D
GERP RS		2.7
Varity_R		0.047
gMVP		0.13
Mutation Taster		=97/3	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

Publications

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Other links and lift over

hg19: chr10-49371585;