Genetic Variant NM_001368397.1:c.1287+25_1287+26dupTT (chrX-12706923-C-CTT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001368397.1(FRMPD4):c.1287+25_1287+26dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.022 ( 48 hom., 192 hem., cov: 10)

Exomes 𝑓: 0.0077 ( 1 hom. 10 hem. )

Consequence

FRMPD4
NM_001368397.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD4	NM_001368397.1 link	c.1287+25_1287+26dupTT		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 link	c.1287+8_1287+9insTT		intron_variant	Intron 12 of 16		NM_001368397.1	ENSP00000502607.1		A0A6Q8PH73

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

1795

AN:

82185

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0615

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0390

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0290

Gnomad SAS

AF:

0.000647

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00562

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.0243

GnomAD2 exomes

AF:

0.00924

AC:

477

AN:

51637

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.00622

Gnomad EAS exome

AF:

0.0122

Gnomad FIN exome

AF:

0.00502

Gnomad NFE exome

AF:

0.00633

Gnomad OTH exome

AF:

0.00746

GnomAD4 exome

AF:

0.00770

AC:

4005

AN:

520195

Hom.:

Cov.:

AF XY:

0.0000668

AC XY:

AN XY:

149597

show subpopulations

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

African (AFR)

AF:

0.0240

AC:

306

AN:

12766

American (AMR)

AF:

0.0159

AC:

305

AN:

19140

Ashkenazi Jewish (ASJ)

AF:

0.00507

AC:

AN:

12426

East Asian (EAS)

AF:

0.0146

AC:

352

AN:

24151

South Asian (SAS)

AF:

0.00433

AC:

120

AN:

27686

European-Finnish (FIN)

AF:

0.00495

AC:

153

AN:

30930

Middle Eastern (MID)

AF:

0.00762

AC:

AN:

2101

European-Non Finnish (NFE)

AF:

0.00677

AC:

2477

AN:

365649

Other (OTH)

AF:

0.00840

AC:

213

AN:

25346

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

309

618

928

1237

1546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.0218

AC:

1795

AN:

82169

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

192

AN XY:

17397

show subpopulations

African (AFR)

AF:

0.0614

AC:

1371

AN:

22318

American (AMR)

AF:

0.0391

AC:

278

AN:

7109

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2110

East Asian (EAS)

AF:

0.0288

AC:

AN:

2608

South Asian (SAS)

AF:

0.000651

AC:

AN:

1535

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2170

Middle Eastern (MID)

AF:

0.00617

AC:

AN:

162

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

42517

Other (OTH)

AF:

0.0241

AC:

AN:

1081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00

Hom.:

295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over