NM_001018071.4:c.3601C>A

Variant names:

• chr10-48163608-G-T
• NM_001018071.4:c.3601C>A

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.3601C>A​(p.Pro1201Thr) 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. 14/22 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)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRMPD2 NM_001018071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.432
• 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: 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=0.08932084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4	c.3601C>A	p.Pro1201Thr	missense_variant	Exon 28 of 29	ENST00000374201.8	NP_001018081.4
FRMPD2	NM_001318191.1	c.3526C>A	p.Pro1176Thr	missense_variant	Exon 26 of 27		NP_001305120.1
FRMPD2	NM_001042512.3	c.634C>A	p.Pro212Thr	missense_variant	Exon 5 of 6		NP_001035977.3
FRMPD2	XM_017015744.2	c.457C>A	p.Pro153Thr	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.3601C>A	p.Pro1201Thr	missense_variant	Exon 28 of 29	1	NM_001018071.4	ENSP00000363317.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.64e-7 AC: 1 AN: 1157014 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 589944

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24092

East Asian (EAS) AF: 0.00 AC: 0 AN: 38156

South Asian (SAS) AF: 0.00 AC: 0 AN: 79984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3540

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 837226

Other (OTH) AF: 0.00 AC: 0 AN: 50036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3601C>A (p.P1201T) alteration is located in exon 28 (coding exon 28) of the FRMPD2 gene. This alteration results from a C to A substitution at nucleotide position 3601, causing the proline (P) at amino acid position 1201 to be replaced by a threonine (T). 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	0.076
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	.;L;.
PhyloP100		0.43
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	.;N;N
REVEL	Benign	0.13
Sift	Benign	0.24	.;T;T
Sift4G	Benign	0.21	.;T;T
Polyphen		1.0, 0.98	.;D;D
Vest4		0.14, 0.15
MutPred		0.13		Gain of phosphorylation at P1201 (P = 0.0505);Gain of phosphorylation at P1201 (P = 0.0505);.;
MVP		0.58
MPC		2.4
ClinPred		0.34	T
GERP RS		1.6
Varity_R		0.059
gMVP		0.23
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

Other links and lift over

hg19: chr10-49371651;