10-48171047-C-T

Variant names:

• chr10-48171047-C-T
• rs1421564961
• NM_001018071.4:c.3385G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001018071.4(FRMPD2):​c.3385G>A​(p.Gly1129Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000095 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRMPD2 NM_001018071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4	c.3385G>A	p.Gly1129Ser	missense_variant	Exon 26 of 29	ENST00000374201.8	NP_001018081.4
FRMPD2	NM_001318191.1	c.3310G>A	p.Gly1104Ser	missense_variant	Exon 24 of 27		NP_001305120.1
FRMPD2	NM_001042512.3	c.418G>A	p.Gly140Ser	missense_variant	Exon 3 of 6		NP_001035977.3
FRMPD2	XM_017015744.2	c.241G>A	p.Gly81Ser	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.3385G>A	p.Gly1129Ser	missense_variant	Exon 26 of 29	1	NM_001018071.4	ENSP00000363317.3

Frequencies

GnomAD3 genomes AF: 0.0000481 AC: 7 AN: 145496 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: 0.00139

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000951 AC: 7 AN: 735824 Hom.: 0 Cov.: 10 AF XY: 0.0000102 AC XY: 4 AN XY: 391500

African (AFR) AF: 0.00 AC: 0 AN: 21288

American (AMR) AF: 0.00 AC: 0 AN: 42872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21228

East Asian (EAS) AF: 0.000194 AC: 7 AN: 36162

South Asian (SAS) AF: 0.00 AC: 0 AN: 71144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 451766

Other (OTH) AF: 0.00 AC: 0 AN: 36356

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000481 AC: 7 AN: 145610 Hom.: 0 Cov.: 23 AF XY: 0.0000568 AC XY: 4 AN XY: 70456

African (AFR) AF: 0.00 AC: 0 AN: 40368

American (AMR) AF: 0.00 AC: 0 AN: 14406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.00139 AC: 7 AN: 5020

South Asian (SAS) AF: 0.00 AC: 0 AN: 4326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65656

Other (OTH) AF: 0.00 AC: 0 AN: 1930

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3385G>A (p.G1129S) 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 3385, causing the glycine (G) at amino acid position 1129 to be replaced by a serine (S). 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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	4.1	.;H;.
PhyloP100		5.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	.;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;D;D
Vest4		0.74, 0.75
MutPred		0.89		Gain of glycosylation at G1129 (P = 0.0599);Gain of glycosylation at G1129 (P = 0.0599);.;
MVP		0.65
MPC		3.1
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.70
gMVP		0.55
Mutation Taster		=65/35	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

Publications

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Other links and lift over

dbSNP: rs1421564961; hg19: chr10-49379090;