chrX-12706923-C-CT

Variant names:

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

Variant summary

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

The NM_001368397.1(FRMPD4):​c.1287+26dupT 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 0.24 (2006 hom., 2707 hem., cov: 10)
  • Exomes 𝑓: 0.098 (43 hom. 222 hem.)
• Consequence: FRMPD4 NM_001368397.1 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 (NFE) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD4	NM_001368397.1	c.1287+26dupT		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+8_1287+9insT		intron_variant	Intron 12 of 16		NM_001368397.1	ENSP00000502607.1

Frequencies

GnomAD3 genomes AF: 0.238 AC: 19475 AN: 81941 Hom.: 2002 Cov.: 10

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0526

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.0572 AC: 2955 AN: 51637 AF XY: 0.00619

Gnomad AFR exome AF: 0.0610

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.0654

Gnomad EAS exome AF: 0.0405

Gnomad FIN exome AF: 0.0534

Gnomad NFE exome AF: 0.0527

Gnomad OTH exome AF: 0.0646

GnomAD4 exome AF: 0.0977 AC: 47800 AN: 489004 Hom.: 43 Cov.: 0 AF XY: 0.00185 AC XY: 222 AN XY: 119990

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

African (AFR) AF: 0.103 AC: 1260 AN: 12242

American (AMR) AF: 0.0715 AC: 1320 AN: 18454

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 853 AN: 11698

East Asian (EAS) AF: 0.0335 AC: 793 AN: 23663

South Asian (SAS) AF: 0.0651 AC: 1637 AN: 25145

European-Finnish (FIN) AF: 0.0961 AC: 2800 AN: 29130

Middle Eastern (MID) AF: 0.0730 AC: 143 AN: 1958

European-Non Finnish (NFE) AF: 0.107 AC: 36684 AN: 342730

Other (OTH) AF: 0.0963 AC: 2310 AN: 23984

⚠️ 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: 0.238 AC: 19483 AN: 81926 Hom.: 2006 Cov.: 10 AF XY: 0.158 AC XY: 2707 AN XY: 17142

African (AFR) AF: 0.221 AC: 4929 AN: 22308

American (AMR) AF: 0.217 AC: 1541 AN: 7103

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 466 AN: 2101

East Asian (EAS) AF: 0.0533 AC: 139 AN: 2610

South Asian (SAS) AF: 0.237 AC: 362 AN: 1527

European-Finnish (FIN) AF: 0.178 AC: 387 AN: 2169

Middle Eastern (MID) AF: 0.292 AC: 47 AN: 161

European-Non Finnish (NFE) AF: 0.266 AC: 11263 AN: 42315

Other (OTH) AF: 0.232 AC: 250 AN: 1077

Alfa AF: 0.0586 Hom.: 295

ClinVar

Not reported in ClinVar

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;