Genetic Variant FHL1:c.-478delA (chrX-136169520-GA-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000543669.5(FHL1):c.-478delA 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 0.000029 ( 0 hom., 0 hem., cov: 0)

Exomes 𝑓: 0.000053 ( 0 hom. 0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.-100-378delA		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.-100-378delA		intron_variant	Intron 1 of 7	5	NM_001159702.3	ENSP00000377710.2		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0000285

AC:

AN:

105232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000687

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000302

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:

0.0000528

AC:

AN:

94704

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29130

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:

3062

American (AMR)

AF:

0.000212

AC:

AN:

4718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2344

East Asian (EAS)

AF:

0.000232

AC:

AN:

4303

South Asian (SAS)

AF:

0.0000743

AC:

AN:

13453

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4357

Middle Eastern (MID)

AF:

0.00

AC:

AN:

345

European-Non Finnish (NFE)

AF:

0.0000349

AC:

AN:

57254

Other (OTH)

AF:

0.00

AC:

AN:

4868

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.010776), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000285

AC:

AN:

105232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28126

show subpopulations

African (AFR)

AF:

0.0000687

AC:

AN:

29106

American (AMR)

AF:

0.00

AC:

AN:

9737

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2561

East Asian (EAS)

AF:

0.000302

AC:

AN:

3316

South Asian (SAS)

AF:

0.00

AC:

AN:

2306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

227

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51311

Other (OTH)

AF:

0.00

AC:

AN:

1419

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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-GA

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