rs760086099

Variant names:

• chrX-12702017-G-A
• rs760086099
• NM_001368397.1:c.1070+7G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001368397.1(FRMPD4):​c.1070+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 113,271 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
• Consequence: FRMPD4 NM_001368397.1 splice_region, intron
• Scores: Splicing: ADA: 0.0002085
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 0 publications found

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]

FRMPD4 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked 104

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368397.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	NM_001368397.1	MANE Select	c.1070+7G>A		splice_region intron	N/A	NP_001355326.1
	FRMPD4	NM_001368395.3		c.1181+7G>A		splice_region intron	N/A	NP_001355324.1
	FRMPD4	NM_001368396.3		c.1076+7G>A		splice_region intron	N/A	NP_001355325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	ENST00000675598.1	MANE Select	c.1070+7G>A		splice_region intron	N/A	ENSP00000502607.1
	FRMPD4	ENST00000380682.5	TSL:1	c.1070+7G>A		splice_region intron	N/A	ENSP00000370057.1
	FRMPD4	ENST00000656302.1		c.1124+7G>A		splice_region intron	N/A	ENSP00000499481.1

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 113271 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000640

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

GnomAD2 exomes AF: 0.00000550 AC: 1 AN: 181796 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 113271 Hom.: 0 Cov.: 24 AF XY: 0.0000283 AC XY: 1 AN XY: 35397

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

African (AFR) AF: 0.0000640 AC: 2 AN: 31230

American (AMR) AF: 0.00 AC: 0 AN: 10796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3627

South Asian (SAS) AF: 0.00 AC: 0 AN: 2784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6277

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53437

Other (OTH) AF: 0.00 AC: 0 AN: 1533

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.056
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

dbSNP: rs760086099; hg19: chrX-12720136;