Genetic Variant FRMPD4:c.1287+20_1287+26delTTTTTTT (chrX-12706923-CTTTTTTT-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001368395.3(FRMPD4):c.1398+20_1398+26delTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 609,146 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 10)

Exomes 𝑓: 0.000034 ( 0 hom. 0 hem. )

Consequence

FRMPD4
NM_001368395.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

Publications

1 publications found

Variant links:

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

FRMPD4 links:

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ACMG classification

Classification was made for transcript

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

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FRMPD4	NM_001368397.1	MANE Select	c.1287+20_1287+26delTTTTTTT	intron	N/A	NP_001355326.1
FRMPD4	NM_001368395.3		c.1398+20_1398+26delTTTTTTT	intron	N/A	NP_001355324.1
FRMPD4	NM_001368396.3		c.1293+20_1293+26delTTTTTTT	intron	N/A	NP_001355325.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FRMPD4	ENST00000675598.1	MANE Select	c.1287+9_1287+15delTTTTTTT	intron	N/A	ENSP00000502607.1
FRMPD4	ENST00000380682.5	TSL:1	c.1287+9_1287+15delTTTTTTT	intron	N/A	ENSP00000370057.1
FRMPD4	ENST00000656302.1		c.1341+9_1341+15delTTTTTTT	intron	N/A	ENSP00000499481.1

Frequencies

GnomAD3 genomes

AF:

0.0000365

AC:

AN:

82297

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00114

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

526864

Hom.:

AF XY:

0.00

AC XY:

AN XY:

154396

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

13070

American (AMR)

AF:

0.00

AC:

AN:

19404

Ashkenazi Jewish (ASJ)

AF:

0.0000799

AC:

AN:

12511

East Asian (EAS)

AF:

0.000122

AC:

AN:

24559

South Asian (SAS)

AF:

0.0000355

AC:

AN:

28167

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31243

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2122

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

370087

Other (OTH)

AF:

0.0000389

AC:

AN:

25701

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000142852), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.322

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000365

AC:

AN:

82282

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

17456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22378

American (AMR)

AF:

0.00

AC:

AN:

7120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2112

East Asian (EAS)

AF:

0.00115

AC:

AN:

2616

South Asian (SAS)

AF:

0.00

AC:

AN:

1536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

162

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

42548

Other (OTH)

AF:

0.00

AC:

AN:

1079

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Splicing

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

Publications

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X-12706923-CTTTTTTTTT-CTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over