chrX-136209946-G-A

Variant names:

• chrX-136209946-G-A
• rs869025431
• NM_001159702.3:c.964G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001440769.1(FHL1):​c.1012G>A​(p.Ala338Thr) 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 benign 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. A338P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001440769.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• 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: Uncertain_significance. The variant received 2 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-136209946-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 222635.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25534466).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440769.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	NM_001159702.3	MANE Plus Clinical	c.964G>A	p.Ala322Thr	missense	Exon 8 of 8	NP_001153174.1
	FHL1	NM_001159699.2	MANE Select	c.812G>A	p.Cys271Tyr	missense	Exon 6 of 6	NP_001153171.1
	FHL1	NM_001440769.1		c.1012G>A	p.Ala338Thr	missense	Exon 7 of 7	NP_001427698.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.964G>A	p.Ala322Thr	missense	Exon 8 of 8	ENSP00000377710.2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.812G>A	p.Cys271Tyr	missense	Exon 6 of 6	ENSP00000359717.1
	FHL1	ENST00000543669.5	TSL:1	c.764G>A	p.Cys255Tyr	missense	Exon 6 of 6	ENSP00000443333.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	Benign	0.070
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.26	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	N
PhyloP100		9.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.040	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.020	B
Vest4		0.15
MutPred		0.12		Gain of glycosylation at A322 (P = 0.0072)
MVP		1.0
MPC		1.2
ClinPred		0.71	D
GERP RS		4.7
Varity_R		0.35
Mutation Taster		=22/78	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: rs869025431; hg19: chrX-135292105;