Genetic Variant FRMPD4:c.1287+26delT (chrX-12706920-TTTCT-TTTC) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_001368397.1(FRMPD4):c.1287+26delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0034 ( 0 hom., 19 hem., cov: 10)

Exomes 𝑓: 0.17 ( 1 hom. 23 hem. )

Consequence

FRMPD4
NM_001368397.1 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.738

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

FRMPD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant X-12706920-TTTCT-TTTC is Benign according to our data. Variant chrX-12706923-CT-C is described in ClinVar as Benign. ClinVar VariationId is 402882.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 19 XL gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FRMPD4	NM_001368397.1	MANE Select	c.1287+26delT	intron	N/A	NP_001355326.1	A0A6Q8PH73
FRMPD4	NM_001368395.3		c.1398+26delT	intron	N/A	NP_001355324.1
FRMPD4	NM_001368396.3		c.1293+26delT	intron	N/A	NP_001355325.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FRMPD4	ENST00000675598.1	MANE Select	c.1287+9delT	intron	N/A	ENSP00000502607.1	A0A6Q8PH73
FRMPD4	ENST00000380682.5	TSL:1	c.1287+9delT	intron	N/A	ENSP00000370057.1	Q14CM0
FRMPD4	ENST00000656302.1		c.1341+9delT	intron	N/A	ENSP00000499481.1	A0A590UJL7

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

278

AN:

82262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00742

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00142

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000646

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00562

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00375

GnomAD2 exomes

AF:

0.200

AC:

10349

AN:

51637

AF XY:

0.00232

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.233

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.169

AC:

75730

AN:

446898

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

89548

show subpopulations

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

African (AFR)

AF:

0.171

AC:

1945

AN:

11364

American (AMR)

AF:

0.154

AC:

2549

AN:

16541

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

1820

AN:

10490

East Asian (EAS)

AF:

0.205

AC:

4100

AN:

20043

South Asian (SAS)

AF:

0.101

AC:

2296

AN:

22631

European-Finnish (FIN)

AF:

0.141

AC:

3744

AN:

26540

Middle Eastern (MID)

AF:

0.173

AC:

309

AN:

1787

European-Non Finnish (NFE)

AF:

0.174

AC:

54936

AN:

315662

Other (OTH)

AF:

0.185

AC:

4031

AN:

21840

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.335

Heterozygous variant carriers

4798

9595

14393

19190

23988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1616

3232

4848

6464

8080

<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:

0.00339

AC:

279

AN:

82247

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

17437

show subpopulations

African (AFR)

AF:

0.00746

AC:

167

AN:

22374

American (AMR)

AF:

0.00478

AC:

AN:

7115

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

2112

East Asian (EAS)

AF:

0.00

AC:

AN:

2614

South Asian (SAS)

AF:

0.000651

AC:

AN:

1536

European-Finnish (FIN)

AF:

0.0120

AC:

AN:

2162

Middle Eastern (MID)

AF:

0.00617

AC:

AN:

162

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

42535

Other (OTH)

AF:

0.00371

AC:

AN:

1078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0255

Hom.:

295

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Publications

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X-12706923-CTTTT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over