chrX-136208453-A-G

Variant names:

• chrX-136208453-A-G
• rs1556639352
• NM_001159702.3:c.502-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001159699.2(FHL1):​c.550-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159699.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.94
• Publications: 0 publications found

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), G2P, Orphanet
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-136208453-A-G is Pathogenic according to our data. Variant chrX-136208453-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 445279.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159699.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	NM_001159702.3	MANE Plus Clinical	c.502-2A>G		splice_acceptor intron	N/A	NP_001153174.1	Q13642-2
	FHL1	NM_001159699.2	MANE Select	c.550-2A>G		splice_acceptor intron	N/A	NP_001153171.1	Q13642-5
	FHL1	NM_001440769.1		c.550-2A>G		splice_acceptor intron	N/A	NP_001427698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.502-2A>G		splice_acceptor intron	N/A	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.550-2A>G		splice_acceptor intron	N/A	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.502-2A>G		splice_acceptor intron	N/A	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	Uruguay Faciocardiomusculoskeletal syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.9
GERP RS		4.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: 2

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

Other links and lift over

dbSNP: rs1556639352; hg19: chrX-135290612;