rs765633648

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-12498671-C-A
• chrX-12498671-C-G
• chrX-12498671-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001368397.1(FRMPD4):​c.42-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000092 (0 hom. 0 hem.)
• Consequence: FRMPD4 NM_001368397.1 intron
• Scores: Splicing: ADA: 0.0003395
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-12498671-C-A is Benign according to our data. Variant chrX-12498671-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435266.

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>A		intron	N/A	NP_001355326.1	A0A6Q8PH73
	FRMPD4	NM_001368395.3		c.153-9C>A		intron	N/A	NP_001355324.1
	FRMPD4	NM_001368396.3		c.42-9C>A		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>A		intron	N/A	ENSP00000502607.1	A0A6Q8PH73
	FRMPD4	ENST00000380682.5	TSL:1	c.42-9C>A		intron	N/A	ENSP00000370057.1	Q14CM0
	FRMPD4	ENST00000656302.1		c.96-9C>A		intron	N/A	ENSP00000499481.1	A0A590UJL7

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000920 AC: 8 AN: 869599 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 244025

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

African (AFR) AF: 0.00 AC: 0 AN: 20813

American (AMR) AF: 0.00 AC: 0 AN: 29421

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16702

East Asian (EAS) AF: 0.00 AC: 0 AN: 27824

South Asian (SAS) AF: 0.00 AC: 0 AN: 44962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3407

European-Non Finnish (NFE) AF: 0.0000122 AC: 8 AN: 654593

Other (OTH) AF: 0.00 AC: 0 AN: 37985

⚠️ 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 Cov.: 20

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	FRMPD4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.17
DANN	Benign	0.74
PhyloP100		-0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.0		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;