10-48178053-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001018071.4(FRMPD2):c.2889T>A(p.Ser963Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRMPD2 NM_001018071.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.95

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMPD2	NM_001018071.4	c.2889T>A	p.Ser963Arg	missense_variant	22/29	ENST00000374201.8
FRMPD2	NM_001318191.1	c.2814T>A	p.Ser938Arg	missense_variant	20/27
FRMPD2	XM_047424652.1	c.2886T>A	p.Ser962Arg	missense_variant	22/22
FRMPD2	XM_047424653.1	c.2796T>A	p.Ser932Arg	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMPD2	ENST00000374201.8	c.2889T>A	p.Ser963Arg	missense_variant	22/29	1	NM_001018071.4	P2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000208 AC: 3 AN: 1444800 Hom.: 1 Cov.: 25 AF XY: 0.00000139 AC XY: 1 AN XY: 719968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

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: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	1.4
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.59	N;N;N
PrimateAI	Uncertain	0.64	T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.88, 0.87
MutPred		0.82		Gain of methylation at S963 (P = 0.0558);Gain of methylation at S963 (P = 0.0558);.;
MVP		0.22
MPC		3.2
ClinPred		0.99	D
GERP RS		-2.1
Varity_R		0.77
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2579678; hg19: chr10-49386096;