rs122459147

Variant names:

• chrX-136207169-T-C
• rs122459147
• NM_001159702.3:c.310T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001159702.3(FHL1):​c.310T>C​(p.Cys104Arg) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C104W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.01
• Publications: 6 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), 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a domain LIM zinc-binding 2 (size 52) in uniprot entity FHL1_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_001159702.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-136207169-T-C is Pathogenic according to our data. Variant chrX-136207169-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11555.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.310T>C	p.Cys104Arg	missense_variant	Exon 4 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.358T>C	p.Cys120Arg	missense_variant	Exon 3 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.310T>C	p.Cys104Arg	missense_variant	Exon 4 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.358T>C	p.Cys120Arg	missense_variant	Exon 3 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.000946 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Myopathy, reducing body, X-linked, childhood-onset Pathogenic:1

Jan 27, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;D;.;D;D;D;.;.;D;.;D;.;.;D;.;D;D;.;.;.;D;D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;.;D;D;D;D;D;D;.;.;.;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.6	H;H;H;.;H;.;.;.;.;H;.;H;.;H;H;.;.;.;H;.;.;.;.;.;H
PhyloP100		8.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-11	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);.;.;.;Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs122459147; hg19: chrX-135289328;