NM_001159702.3:c.175C>A

Variant names:

• chrX-136207034-C-A
• rs1343871742
• NM_001159702.3:c.175C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001159702.3(FHL1):​c.175C>A​(p.Arg59Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159702.3. 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.175C>A	p.Arg59Ser	missense	Exon 4 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001159699.2	MANE Select	c.223C>A	p.Arg75Ser	missense	Exon 3 of 6	NP_001153171.1	Q13642-5
	FHL1	NM_001440769.1		c.223C>A	p.Arg75Ser	missense	Exon 3 of 7	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.175C>A	p.Arg59Ser	missense	Exon 4 of 8	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.223C>A	p.Arg75Ser	missense	Exon 3 of 6	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.175C>A	p.Arg59Ser	missense	Exon 3 of 6	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111866 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000285

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 Cov.: 31

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111866 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34048

African (AFR) AF: 0.00 AC: 0 AN: 30757

American (AMR) AF: 0.00 AC: 0 AN: 10646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3503

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53141

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.72		Loss of MoRF binding (P = 0.0572)
MVP		1.0
MPC		1.4
ClinPred		0.85	D
GERP RS		5.1
Varity_R		0.87
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1343871742; hg19: chrX-135289193;