chrX-12706923-CTT-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001368397.1(FRMPD4):​c.1287+25_1287+26delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 555,006 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 0 hem., cov: 10)
  • Exomes 𝑓: 0.051 (0 hom. 1 hem.)
• Consequence: FRMPD4 NM_001368397.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD4	NM_001368397.1	c.1287+25_1287+26delTT		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+9_1287+10delTT		intron_variant	Intron 12 of 16		NM_001368397.1	ENSP00000502607.1

Frequencies

GnomAD3 genomes AF: 0.000255 AC: 21 AN: 82263 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.0000895

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000562

Gnomad ASJ AF: 0.000474

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0915 AC: 4726 AN: 51637 AF XY: 0.00

Gnomad AFR exome AF: 0.0967

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0876

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0390

Gnomad NFE exome AF: 0.0929

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0505 AC: 23886 AN: 472758 Hom.: 0 AF XY: 0.00000808 AC XY: 1 AN XY: 123770

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

African (AFR) AF: 0.0546 AC: 644 AN: 11794

American (AMR) AF: 0.0642 AC: 1104 AN: 17204

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 608 AN: 11011

East Asian (EAS) AF: 0.0603 AC: 1260 AN: 20904

South Asian (SAS) AF: 0.0384 AC: 943 AN: 24529

European-Finnish (FIN) AF: 0.0361 AC: 1015 AN: 28105

Middle Eastern (MID) AF: 0.0392 AC: 74 AN: 1889

European-Non Finnish (NFE) AF: 0.0508 AC: 16998 AN: 334374

Other (OTH) AF: 0.0540 AC: 1240 AN: 22948

⚠️ 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: 0.000255 AC: 21 AN: 82248 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 17448

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

African (AFR) AF: 0.0000894 AC: 2 AN: 22371

American (AMR) AF: 0.000562 AC: 4 AN: 7115

Ashkenazi Jewish (ASJ) AF: 0.000474 AC: 1 AN: 2110

East Asian (EAS) AF: 0.00 AC: 0 AN: 2616

South Asian (SAS) AF: 0.00 AC: 0 AN: 1536

European-Finnish (FIN) AF: 0.00277 AC: 6 AN: 2163

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.000188 AC: 8 AN: 42537

Other (OTH) AF: 0.00 AC: 0 AN: 1079

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0144 Hom.: 295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
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;