X-12706923-CTTTTTTTTT-CTTTTTTTTTTT

Variant names:

• chrX-12706923-C-CTT
• rs746601138
• NM_001368397.1:c.1287+25_1287+26dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001368395.3(FRMPD4):​c.1398+25_1398+26dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.022 (48 hom., 192 hem., cov: 10)
  • Exomes 𝑓: 0.0077 (1 hom. 10 hem.)
• Consequence: FRMPD4 NM_001368395.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0587 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368395.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	NM_001368397.1	MANE Select	c.1287+25_1287+26dupTT		intron	N/A	NP_001355326.1
	FRMPD4	NM_001368395.3		c.1398+25_1398+26dupTT		intron	N/A	NP_001355324.1
	FRMPD4	NM_001368396.3		c.1293+25_1293+26dupTT		intron	N/A	NP_001355325.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	ENST00000675598.1	MANE Select	c.1287+8_1287+9insTT		intron	N/A	ENSP00000502607.1
	FRMPD4	ENST00000380682.5	TSL:1	c.1287+8_1287+9insTT		intron	N/A	ENSP00000370057.1
	FRMPD4	ENST00000656302.1		c.1341+8_1341+9insTT		intron	N/A	ENSP00000499481.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 1795 AN: 82185 Hom.: 48 Cov.: 10

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.000647

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00562

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0243

GnomAD2 exomes AF: 0.00924 AC: 477 AN: 51637 AF XY: 0.00155

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.00622

Gnomad EAS exome AF: 0.0122

Gnomad FIN exome AF: 0.00502

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.00746

GnomAD4 exome AF: 0.00770 AC: 4005 AN: 520195 Hom.: 1 Cov.: 0 AF XY: 0.0000668 AC XY: 10 AN XY: 149597

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

African (AFR) AF: 0.0240 AC: 306 AN: 12766

American (AMR) AF: 0.0159 AC: 305 AN: 19140

Ashkenazi Jewish (ASJ) AF: 0.00507 AC: 63 AN: 12426

East Asian (EAS) AF: 0.0146 AC: 352 AN: 24151

South Asian (SAS) AF: 0.00433 AC: 120 AN: 27686

European-Finnish (FIN) AF: 0.00495 AC: 153 AN: 30930

Middle Eastern (MID) AF: 0.00762 AC: 16 AN: 2101

European-Non Finnish (NFE) AF: 0.00677 AC: 2477 AN: 365649

Other (OTH) AF: 0.00840 AC: 213 AN: 25346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0218 AC: 1795 AN: 82169 Hom.: 48 Cov.: 10 AF XY: 0.0110 AC XY: 192 AN XY: 17397

African (AFR) AF: 0.0614 AC: 1371 AN: 22318

American (AMR) AF: 0.0391 AC: 278 AN: 7109

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2110

East Asian (EAS) AF: 0.0288 AC: 75 AN: 2608

South Asian (SAS) AF: 0.000651 AC: 1 AN: 1535

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2170

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

European-Non Finnish (NFE) AF: 0.00101 AC: 43 AN: 42517

Other (OTH) AF: 0.0241 AC: 26 AN: 1081

Alfa AF: 0.00 Hom.: 295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746601138; hg19: chrX-12725042;