Genetic Variant FHL1:c.-479_-478dupAA (chrX-136169520-G-GAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000543669.5(FHL1):c.-479_-478dupAA variant causes a 5 prime UTR 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 0.00036 ( 0 hom., 8 hem., cov: 0)

Exomes 𝑓: 0.0054 ( 0 hom. 17 hem. )

Consequence

FHL1
ENST00000543669.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0940

Publications

1 publications found

Variant links:

Genes affected

FHL1 (HGNC:3702): (four and a half LIM domains 1) This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. Expression of these family members occurs in a cell- and tissue-specific mode and these proteins are involved in many cellular processes. Mutations in this gene have been found in patients with Emery-Dreifuss muscular dystrophy. Multiple alternately spliced transcript variants which encode different protein isoforms have been described.[provided by RefSeq, Nov 2009]

FHL1 Gene-Disease associations (from GenCC):

X-linked myopathy with postural muscle atrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
myopathy, reducing body, X-linked, early-onset, severe
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
reducing body myopathy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Emery-Dreifuss muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked scapuloperoneal muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

FHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000361 (38/105250) while in subpopulation SAS AF = 0.00437 (10/2290). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.-100-379_-100-378dupAA		intron_variant	Intron 1 of 7	ENST00000394155.8	NP_001153174.1	Q13642-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 link	c.-100-379_-100-378dupAA		intron_variant	Intron 1 of 7	5	NM_001159702.3	ENSP00000377710.2		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

105214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000378

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000514

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000302

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000175

Gnomad OTH

AF:

0.00141

GnomAD4 exome

AF:

0.00543

AC:

496

AN:

91282

Hom.:

Cov.:

AF XY:

0.000621

AC XY:

AN XY:

27364

show subpopulations

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

African (AFR)

AF:

0.00331

AC:

AN:

3022

American (AMR)

AF:

0.00305

AC:

AN:

4584

Ashkenazi Jewish (ASJ)

AF:

0.00398

AC:

AN:

2264

East Asian (EAS)

AF:

0.00237

AC:

AN:

4214

South Asian (SAS)

AF:

0.00620

AC:

AN:

12899

European-Finnish (FIN)

AF:

0.00663

AC:

AN:

4222

Middle Eastern (MID)

AF:

0.00896

AC:

AN:

335

European-Non Finnish (NFE)

AF:

0.00574

AC:

316

AN:

55013

Other (OTH)

AF:

0.00550

AC:

AN:

4729

⚠️ 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: 0.258

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000361

AC:

AN:

105250

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

AN XY:

28156

show subpopulations

African (AFR)

AF:

0.000377

AC:

AN:

29163

American (AMR)

AF:

0.000513

AC:

AN:

9744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2560

East Asian (EAS)

AF:

0.000302

AC:

AN:

3306

South Asian (SAS)

AF:

0.00437

AC:

AN:

2290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

205

European-Non Finnish (NFE)

AF:

0.000175

AC:

AN:

51300

Other (OTH)

AF:

0.00139

AC:

AN:

1437

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1688

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.094

Splicing

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

Publications

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X-136169520-GAA-GAAAA

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