10-48178053-A-T

Variant names:

• chr10-48178053-A-T
• rs2579678
• NM_001018071.4:c.2889T>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018071.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD2	NM_001018071.4	MANE Select	c.2889T>A	p.Ser963Arg	missense	Exon 22 of 29	NP_001018081.4	Q68DX3-1
	FRMPD2	NM_001318191.1		c.2814T>A	p.Ser938Arg	missense	Exon 20 of 27	NP_001305120.1	Q68DX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD2	ENST00000374201.8	TSL:1 MANE Select	c.2889T>A	p.Ser963Arg	missense	Exon 22 of 29	ENSP00000363317.3	Q68DX3-1
	FRMPD2	ENST00000463706.1	TSL:1	n.172T>A		non_coding_transcript_exon	Exon 2 of 9
	FRMPD2	ENST00000636244.1	TSL:5	c.2889T>A	p.Ser963Arg	missense	Exon 22 of 30	ENSP00000490201.1	A0A1B0GUQ4

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

African (AFR) AF: 0.00 AC: 0 AN: 33048

American (AMR) AF: 0.0000448 AC: 2 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 85764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098538

Other (OTH) AF: 0.00 AC: 0 AN: 59696

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	L
PhyloP100		-2.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.82		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
Mutation Taster		=59/40	polymorphism

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

Other links and lift over

dbSNP: rs2579678; hg19: chr10-49386096;