X-136209862-TC-TCC

Variant names:

• chrX-136209862-T-TC
• rs368428875
• NM_001159702.3:c.889-3dupC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PVS1_Strong PM2 BP6_Moderate

The NM_001159699.2(FHL1):​c.737-3dupC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,170,172 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: FHL1 NM_001159699.2 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.111
• Publications: 1 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 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.6655444 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: tctttttttttcccccccAGggt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-136209862-T-TC is Benign according to our data. Variant chrX-136209862-T-TC is described in ClinVar as Benign. ClinVar VariationId is 2893227.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_001159702.3	MANE Plus Clinical	c.889-3dupC		splice_acceptor intron	N/A	NP_001153174.1	Q13642-2
	FHL1	NM_001159699.2	MANE Select	c.737-3dupC		splice_acceptor intron	N/A	NP_001153171.1	Q13642-5
	FHL1	NM_001440769.1		c.937-3dupC		splice_acceptor intron	N/A	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.889-9_889-8insC		splice_region intron	N/A	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.737-9_737-8insC		splice_region intron	N/A	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.689-9_689-8insC		splice_region intron	N/A	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes AF: 0.00000916 AC: 1 AN: 109165 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000404

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000178 AC: 3 AN: 168269 AF XY: 0.0000343

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000402

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000283 AC: 3 AN: 1061007 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 344357

African (AFR) AF: 0.00 AC: 0 AN: 25756

American (AMR) AF: 0.00 AC: 0 AN: 33687

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18802

East Asian (EAS) AF: 0.00 AC: 0 AN: 29088

South Asian (SAS) AF: 0.00 AC: 0 AN: 51990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3581

European-Non Finnish (NFE) AF: 0.00000245 AC: 2 AN: 814757

Other (OTH) AF: 0.0000224 AC: 1 AN: 44580

GnomAD4 genome AF: 0.00000916 AC: 1 AN: 109165 Hom.: 0 Cov.: 20 AF XY: 0.0000316 AC XY: 1 AN XY: 31681

African (AFR) AF: 0.00 AC: 0 AN: 30019

American (AMR) AF: 0.00 AC: 0 AN: 10237

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3491

South Asian (SAS) AF: 0.000404 AC: 1 AN: 2475

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5613

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52329

Other (OTH) AF: 0.00 AC: 0 AN: 1470

Alfa AF: 0.00 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Benign

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
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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: rs368428875; hg19: chrX-135292021;