rs1556639771

Variant names:

• chrX-136210008-T-A
• rs1556639771
• NM_001159699.2:c.874T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001159699.2(FHL1):​c.874T>A​(p.Cys292Ser) variant causes a missense 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. 10/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C292Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136210009-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1459000.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant X-136210008-T-A is Pathogenic according to our data. Variant chrX-136210008-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 537357.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_001159699.2	MANE Select	c.874T>A	p.Cys292Ser	missense	Exon 6 of 6	NP_001153171.1	Q13642-5
	FHL1	NM_001159702.3	MANE Plus Clinical	c.*54T>A		3_prime_UTR	Exon 8 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001159701.2		c.913T>A	p.Cys305Ser	missense	Exon 6 of 6	NP_001153173.1	Q13642-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.874T>A	p.Cys292Ser	missense	Exon 6 of 6	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.826T>A	p.Cys276Ser	missense	Exon 6 of 6	ENSP00000443333.1	Q13642-1
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.*54T>A		3_prime_UTR	Exon 8 of 8	ENSP00000377710.2	Q13642-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	27
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.7
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
MutPred		0.62		Gain of disorder (P = 0.0035)
MVP		1.0
ClinPred		0.99	D
GERP RS		5.6
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1556639771; hg19: chrX-135292167;