rs139449383

chrX-12614847-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001368397.1(FRMPD4):c.388G>A(p.Ala130Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,181,909 control chromosomes in the GnomAD database, including 1 homozygotes. There are 339 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., 32 hem., cov: 22)
  • Exomes 𝑓: 0.00086 (1 hom. 307 hem.)
• Consequence: FRMPD4 NM_001368397.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.76

Genes affected

FRMPD4 (HGNC:29007): (FERM and PDZ domain containing 4) This gene encodes a multi-domain (WW, PDZ, FERM) containing protein. Through its interaction with other proteins (such as PSD-95), it functions as a positive regulator of dendritic spine morphogenesis and density, and is required for the maintenance of excitatory synaptic transmission. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006225556).
• BP6: Variant X-12614847-G-A is Benign according to our data. Variant chrX-12614847-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-12614847-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMPD4	NM_001368397.1	c.388G>A	p.Ala130Thr	missense_variant	4/17	ENST00000675598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMPD4	ENST00000675598.1	c.388G>A	p.Ala130Thr	missense_variant	4/17		NM_001368397.1	P2

Frequencies

GnomAD3 genomes AF: 0.000990 AC: 110 AN: 111056 Hom.: 0 Cov.: 22 AF XY: 0.000963 AC XY: 32 AN XY: 33242

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00418

Gnomad ASJ AF: 0.00643

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000391

Gnomad FIN AF: 0.000841

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000755

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000904 AC: 164 AN: 181428 Hom.: 1 AF XY: 0.000879 AC XY: 58 AN XY: 65962

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000438

Gnomad NFE exome AF: 0.000900

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.000857 AC: 918 AN: 1070799 Hom.: 1 Cov.: 24 AF XY: 0.000906 AC XY: 307 AN XY: 338745

Gnomad4 AFR exome AF: 0.0000771

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00553

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000188

Gnomad4 FIN exome AF: 0.000494

Gnomad4 NFE exome AF: 0.000823

Gnomad4 OTH exome AF: 0.00155

GnomAD4 genome AF: 0.000990 AC: 110 AN: 111110 Hom.: 0 Cov.: 22 AF XY: 0.000961 AC XY: 32 AN XY: 33306

Gnomad4 AFR AF: 0.0000328

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00643

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000392

Gnomad4 FIN AF: 0.000841

Gnomad4 NFE AF: 0.000755

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.00108 Hom.: 48

Bravo AF: 0.00122

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000873 AC: 106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.021	T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.36	N;.
MutationTaster	Benign	0.80	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.050	N;.
REVEL	Benign	0.10
Sift	Benign	0.38	T;.
Sift4G	Benign	0.37	T;T
Polyphen		0.012	B;.
Vest4		0.17
MVP		0.40
MPC		0.88
ClinPred		0.0097	T
GERP RS		4.6
Varity_R		0.083
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs139449383; hg19: chrX-12632966;