rs144170600

Positions:

• chrX-12717058-A-G

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.2599A>G​(p.Asn867Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000382 in 1,206,761 control chromosomes in the GnomAD database, including 1 homozygotes. There are 220 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00040 (1 hom. 211 hem.)
• Consequence: FRMPD4 NM_001368397.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.65

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=0.0034191012).
• BP6: Variant X-12717058-A-G is Benign according to our data. Variant chrX-12717058-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 435268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-12717058-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMPD4	NM_001368397.1	c.2599A>G	p.Asn867Asp	missense_variant	15/17	ENST00000675598.1	NP_001355326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMPD4	ENST00000675598.1	c.2599A>G	p.Asn867Asp	missense_variant	15/17		NM_001368397.1	ENSP00000502607	P2

Frequencies

GnomAD3 genomes AF: 0.000239 AC: 27 AN: 112828 Hom.: 0 Cov.: 23 AF XY: 0.000286 AC XY: 10 AN XY: 34972

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000928

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00328

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000281

Gnomad OTH AF: 0.000657

GnomAD3 exomes AF: 0.000664 AC: 120 AN: 180770 Hom.: 0 AF XY: 0.00103 AC XY: 68 AN XY: 65708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.000408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00411

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000398 AC: 435 AN: 1093882 Hom.: 1 Cov.: 31 AF XY: 0.000587 AC XY: 211 AN XY: 359528

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.000776

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.000610

GnomAD4 genome AF: 0.000230 AC: 26 AN: 112879 Hom.: 0 Cov.: 23 AF XY: 0.000257 AC XY: 9 AN XY: 35033

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000927

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00292

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000281

Gnomad4 OTH AF: 0.000649

Alfa AF: 0.000417 Hom.: 17

Bravo AF: 0.000162

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000906 AC: 110

EpiCase AF: 0.000493

EpiControl AF: 0.000653

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, X-linked 104 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 16, 2015

- -

FRMPD4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	7.8
DANN	Benign	0.28
DEOGEN2	Benign	0.026	T;T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.50	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.8	N;.
REVEL	Benign	0.13
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.055
MVP		0.10
MPC		0.14
ClinPred		0.0094	T
GERP RS		2.3
Varity_R		0.049
gMVP		0.23

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: rs144170600; hg19: chrX-12735177;