X-12498671-C-T

Variant names:

• chrX-12498671-C-T
• rs765633648
• NM_001368397.1:c.42-9C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001368397.1(FRMPD4):​c.42-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0010 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FRMPD4 NM_001368397.1 intron
• Scores: Splicing: ADA: 0.0001280
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.593
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	NM_001368397.1	MANE Select	c.42-9C>T		intron	N/A	NP_001355326.1	A0A6Q8PH73
	FRMPD4	NM_001368395.3		c.153-9C>T		intron	N/A	NP_001355324.1
	FRMPD4	NM_001368396.3		c.42-9C>T		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.42-9C>T		intron	N/A	ENSP00000502607.1	A0A6Q8PH73
	FRMPD4	ENST00000380682.5	TSL:1	c.42-9C>T		intron	N/A	ENSP00000370057.1	Q14CM0
	FRMPD4	ENST00000656302.1		c.96-9C>T		intron	N/A	ENSP00000499481.1	A0A590UJL7

Frequencies

GnomAD3 genomes AF: 0.000635 AC: 59 AN: 92867 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000430

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00479

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000614

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00468 AC: 632 AN: 134965 AF XY: 0.00

Gnomad AFR exome AF: 0.00389

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.00385

Gnomad EAS exome AF: 0.00341

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.00604

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00101 AC: 875 AN: 867019 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 242625

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

African (AFR) AF: 0.00276 AC: 57 AN: 20687

American (AMR) AF: 0.00584 AC: 170 AN: 29091

Ashkenazi Jewish (ASJ) AF: 0.00102 AC: 17 AN: 16640

East Asian (EAS) AF: 0.000108 AC: 3 AN: 27806

South Asian (SAS) AF: 0.000717 AC: 32 AN: 44621

European-Finnish (FIN) AF: 0.0113 AC: 370 AN: 32822

Middle Eastern (MID) AF: 0.00118 AC: 4 AN: 3394

European-Non Finnish (NFE) AF: 0.000284 AC: 186 AN: 654075

Other (OTH) AF: 0.000950 AC: 36 AN: 37883

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000635 AC: 59 AN: 92886 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 23772

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

African (AFR) AF: 0.000397 AC: 10 AN: 25166

American (AMR) AF: 0.00 AC: 0 AN: 8678

Ashkenazi Jewish (ASJ) AF: 0.000430 AC: 1 AN: 2326

East Asian (EAS) AF: 0.00 AC: 0 AN: 2998

South Asian (SAS) AF: 0.00 AC: 0 AN: 1941

European-Finnish (FIN) AF: 0.00479 AC: 20 AN: 4173

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.000614 AC: 28 AN: 45592

Other (OTH) AF: 0.00 AC: 0 AN: 1252

⚠️ 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: 0.0216 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.3
DANN	Benign	0.74
PhyloP100		-0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs765633648; hg19: chrX-12516790;