chrX-12706923-CT-C

Variant names:

• chrX-12706923-CT-C
• rs746601138
• NM_001368397.1:c.1287+26delT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001368397.1(FRMPD4):​c.1287+26delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., 19 hem., cov: 10)
  • Exomes 𝑓: 0.17 (1 hom. 23 hem.)
• Consequence: FRMPD4 NM_001368397.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.738
• Publications: 1 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 -6 ACMG points.

• BP6: Variant X-12706923-CT-C is Benign according to our data. Variant chrX-12706923-CT-C is described in ClinVar as [Benign]. Clinvar id is 402882.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD4	NM_001368397.1	c.1287+26delT		intron_variant	Intron 12 of 16	ENST00000675598.1	NP_001355326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMPD4	ENST00000675598.1	c.1287+9delT		intron_variant	Intron 12 of 16		NM_001368397.1	ENSP00000502607.1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 278 AN: 82262 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.00742

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00142

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000646

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00562

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00375

GnomAD2 exomes AF: 0.200 AC: 10349 AN: 51637 AF XY: 0.00232

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.169 AC: 75730 AN: 446898 Hom.: 1 Cov.: 0 AF XY: 0.000257 AC XY: 23 AN XY: 89548

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

African (AFR) AF: 0.171 AC: 1945 AN: 11364

American (AMR) AF: 0.154 AC: 2549 AN: 16541

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 1820 AN: 10490

East Asian (EAS) AF: 0.205 AC: 4100 AN: 20043

South Asian (SAS) AF: 0.101 AC: 2296 AN: 22631

European-Finnish (FIN) AF: 0.141 AC: 3744 AN: 26540

Middle Eastern (MID) AF: 0.173 AC: 309 AN: 1787

European-Non Finnish (NFE) AF: 0.174 AC: 54936 AN: 315662

Other (OTH) AF: 0.185 AC: 4031 AN: 21840

⚠️ 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 AF: 0.00339 AC: 279 AN: 82247 Hom.: 0 Cov.: 10 AF XY: 0.00109 AC XY: 19 AN XY: 17437

African (AFR) AF: 0.00746 AC: 167 AN: 22374

American (AMR) AF: 0.00478 AC: 34 AN: 7115

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 3 AN: 2112

East Asian (EAS) AF: 0.00 AC: 0 AN: 2614

South Asian (SAS) AF: 0.000651 AC: 1 AN: 1536

European-Finnish (FIN) AF: 0.0120 AC: 26 AN: 2162

Middle Eastern (MID) AF: 0.00617 AC: 1 AN: 162

European-Non Finnish (NFE) AF: 0.00101 AC: 43 AN: 42535

Other (OTH) AF: 0.00371 AC: 4 AN: 1078

Alfa AF: 0.0255 Hom.: 295

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs746601138; hg19: chrX-12725042; COSMIC: COSV66225247;