10-48180942-T-C

Position:

• chr10-48180942-T-C

Variant summary

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

The NM_001018071.4(FRMPD2):​c.2651A>G​(p.Asp884Gly) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRMPD2 NM_001018071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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

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=0.12755838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMPD2	NM_001018071.4	c.2651A>G	p.Asp884Gly	missense_variant	21/29	ENST00000374201.8
FRMPD2	NM_001318191.1	c.2576A>G	p.Asp859Gly	missense_variant	19/27
FRMPD2	XM_047424652.1	c.2648A>G	p.Asp883Gly	missense_variant	21/22
FRMPD2	XM_047424653.1	c.2558A>G	p.Asp853Gly	missense_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMPD2	ENST00000374201.8	c.2651A>G	p.Asp884Gly	missense_variant	21/29	1	NM_001018071.4	P2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000249 AC: 2 AN: 801642 Hom.: 0 Cov.: 11 AF XY: 0.00000235 AC XY: 1 AN XY: 425276

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000545

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

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

Mar 06, 2023

The c.2651A>G (p.D884G) alteration is located in exon 21 (coding exon 21) of the FRMPD2 gene. This alteration results from a A to G substitution at nucleotide position 2651, causing the aspartic acid (D) at amino acid position 884 to be replaced by a glycine (G). 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	0.084
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.031	T;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.63	.;N;.
MutationTaster	Benign	0.87	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	.;D;D
REVEL	Benign	0.061
Sift	Benign	0.21	.;T;T
Sift4G	Benign	0.46	.;T;T
Polyphen		0.016, 0.041	.;B;B
Vest4		0.11, 0.13
MutPred		0.26		Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);.;
MVP		0.49
MPC		0.039
ClinPred		0.055	T
GERP RS		2.6
Varity_R		0.10
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1251260080; hg19: chr10-49388985;