NM_001159702.3:c.2T>C

Variant names:

• chrX-136206434-T-C
• NM_001159702.3:c.2T>C

Variant summary

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

The NM_001159702.3(FHL1):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: FHL1 NM_001159702.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.26
• 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: Start lost variant, next in-frame start position is after 77 pathogenic variants. Next in-frame start position is after 307 codons. Genomic position: 136209901. Lost 0.945 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-136206434-T-C is Pathogenic according to our data. Variant chrX-136206434-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2861396.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2T>C	p.Met1?	start_lost	Exon 3 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001159699.2	MANE Select	c.50T>C	p.Met17Thr	missense	Exon 2 of 6	NP_001153171.1	Q13642-5
	FHL1	NM_001369326.1		c.2T>C	p.Met1?	start_lost	Exon 3 of 8	NP_001356255.1	Q13642-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.2T>C	p.Met1?	start_lost	Exon 3 of 8	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000543669.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 6	ENSP00000443333.1	Q13642-1
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.50T>C	p.Met17Thr	missense	Exon 2 of 6	ENSP00000359717.1	Q13642-5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

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	0.58
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.099	D
PhyloP100		6.3
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.62		Gain of catalytic residue at M1 (P = 0.0439)
MVP		0.93
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		-0.038	Neutral
Varity_R		0.84
Mutation Taster		=15/185	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

hg19: chrX-135288593; COSMIC: COSV100600644; COSMIC: COSV100600644;