10-48171068-C-T

Variant names:

• chr10-48171068-C-T
• rs1164474634
• NM_001018071.4:c.3364G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001018071.4(FRMPD2):​c.3364G>A​(p.Glu1122Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000097 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRMPD2 NM_001018071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2009885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4	c.3364G>A	p.Glu1122Lys	missense_variant	Exon 26 of 29	ENST00000374201.8	NP_001018081.4
FRMPD2	NM_001318191.1	c.3289G>A	p.Glu1097Lys	missense_variant	Exon 24 of 27		NP_001305120.1
FRMPD2	NM_001042512.3	c.397G>A	p.Glu133Lys	missense_variant	Exon 3 of 6		NP_001035977.3
FRMPD2	XM_017015744.2	c.220G>A	p.Glu74Lys	missense_variant	Exon 3 of 6		XP_016871233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMPD2	ENST00000374201.8	c.3364G>A	p.Glu1122Lys	missense_variant	Exon 26 of 29	1	NM_001018071.4	ENSP00000363317.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 146698 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000975 AC: 7 AN: 718048 Hom.: 0 Cov.: 9 AF XY: 0.00000262 AC XY: 1 AN XY: 381770

African (AFR) AF: 0.00 AC: 0 AN: 20774

American (AMR) AF: 0.000165 AC: 7 AN: 42500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21068

East Asian (EAS) AF: 0.00 AC: 0 AN: 35948

South Asian (SAS) AF: 0.00 AC: 0 AN: 70656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 436518

Other (OTH) AF: 0.00 AC: 0 AN: 35712

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 146698 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 71038

African (AFR) AF: 0.00 AC: 0 AN: 40404

American (AMR) AF: 0.00 AC: 0 AN: 14546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.00 AC: 0 AN: 4374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66198

Other (OTH) AF: 0.00 AC: 0 AN: 1926

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3364G>A (p.E1122K) alteration is located in exon 26 (coding exon 26) of the FRMPD2 gene. This alteration results from a G to A substitution at nucleotide position 3364, causing the glutamic acid (E) at amino acid position 1122 to be replaced by a lysine (K). 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	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	.;N;.
PhyloP100		3.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	.;D;D
REVEL	Benign	0.058
Sift	Benign	0.034	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		0.28, 0.20	.;B;B
Vest4		0.31, 0.31
MutPred		0.52		Gain of ubiquitination at E1122 (P = 0.0155);Gain of ubiquitination at E1122 (P = 0.0155);.;
MVP		0.13
MPC		2.4
ClinPred		0.73	D
GERP RS		0.36
Varity_R		0.11
gMVP		0.23
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1164474634; hg19: chr10-49379111;