rs1314023088

Variant names:

• chrX-136207892-A-AGGG
• rs1314023088
• NM_001159702.3:c.434_436dupGGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PM4_Supporting BS2

The NM_001440769.1(FHL1):​c.482_484dupGGG​(p.Gly161dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000991 in 1,210,948 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 4 hem.)
• Consequence: FHL1 NM_001440769.1 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.84
• 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), 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_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001440769.1
• PM4: Nonframeshift variant in NON repetitive region in NM_001440769.1. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

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.434_436dupGGG	p.Gly145dup	disruptive_inframe_insertion	Exon 5 of 8	NP_001153174.1
	FHL1	NM_001159699.2	MANE Select	c.482_484dupGGG	p.Gly161dup	disruptive_inframe_insertion	Exon 4 of 6	NP_001153171.1
	FHL1	NM_001440769.1		c.482_484dupGGG	p.Gly161dup	disruptive_inframe_insertion	Exon 4 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.434_436dupGGG	p.Gly145dup	disruptive_inframe_insertion	Exon 5 of 8	ENSP00000377710.2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.482_484dupGGG	p.Gly161dup	disruptive_inframe_insertion	Exon 4 of 6	ENSP00000359717.1
	FHL1	ENST00000543669.5	TSL:1	c.434_436dupGGG	p.Gly145dup	disruptive_inframe_insertion	Exon 4 of 6	ENSP00000443333.1

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112784 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.000656

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183454 AF XY: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098164 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363518

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842055

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112784 Hom.: 0 Cov.: 23 AF XY: 0.0000286 AC XY: 1 AN XY: 34940

African (AFR) AF: 0.00 AC: 0 AN: 31086

American (AMR) AF: 0.00 AC: 0 AN: 10757

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.00 AC: 0 AN: 2723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6223

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53318

Other (OTH) AF: 0.000656 AC: 1 AN: 1525

Alfa AF: 0.00 Hom.: 0

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
PhyloP100		6.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1314023088; hg19: chrX-135290051;