rs3215593

Variant names:

• chrX-136170075-AC-A
• rs3215593
• NM_001159702.3:c.-27+97delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001159702.3(FHL1):​c.-27+97delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 196,933 control chromosomes in the GnomAD database, including 34,795 homozygotes. There are 55,407 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (18871 hom., 21327 hem., cov: 0)
  • Exomes 𝑓: 0.75 (34795 hom. 55407 hem.)
  • Failed GnomAD Quality Control
• Consequence: FHL1 NM_001159702.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.558
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-136170075-AC-A is Benign according to our data. Variant chrX-136170075-AC-A is described in ClinVar as Benign. ClinVar VariationId is 1304791.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

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.-27+97delC		intron	N/A	NP_001153174.1	Q13642-2
	FHL1	NM_001369326.1		c.-27+97delC		intron	N/A	NP_001356255.1	Q13642-2
	FHL1	NM_001369327.2		c.-27+97delC		intron	N/A	NP_001356256.1	Q13642-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.-27+96delC		intron	N/A	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000543669.5	TSL:1	c.-27+96delC		intron	N/A	ENSP00000443333.1	Q13642-1
	FHL1	ENST00000651089.1		c.-169+96delC		intron	N/A	ENSP00000498684.1	Q13642-2

Frequencies

GnomAD3 genomes AF: 0.684 AC: 74498 AN: 108921 Hom.: 18870 Cov.: 0

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.650

GnomAD4 exome AF: 0.749 AC: 147470 AN: 196933 Hom.: 34795 AF XY: 0.755 AC XY: 55407 AN XY: 73425

African (AFR) AF: 0.501 AC: 2923 AN: 5836

American (AMR) AF: 0.696 AC: 12164 AN: 17478

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 4684 AN: 6738

East Asian (EAS) AF: 0.615 AC: 4006 AN: 6516

South Asian (SAS) AF: 0.701 AC: 22020 AN: 31394

European-Finnish (FIN) AF: 0.828 AC: 7327 AN: 8845

Middle Eastern (MID) AF: 0.590 AC: 1139 AN: 1931

European-Non Finnish (NFE) AF: 0.794 AC: 86185 AN: 108564

Other (OTH) AF: 0.729 AC: 7022 AN: 9631

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.684 AC: 74524 AN: 108975 Hom.: 18871 Cov.: 0 AF XY: 0.681 AC XY: 21327 AN XY: 31311

African (AFR) AF: 0.498 AC: 14883 AN: 29883

American (AMR) AF: 0.675 AC: 6867 AN: 10176

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 1755 AN: 2618

East Asian (EAS) AF: 0.604 AC: 2081 AN: 3447

South Asian (SAS) AF: 0.657 AC: 1605 AN: 2444

European-Finnish (FIN) AF: 0.818 AC: 4573 AN: 5592

Middle Eastern (MID) AF: 0.622 AC: 135 AN: 217

European-Non Finnish (NFE) AF: 0.785 AC: 41184 AN: 52460

Other (OTH) AF: 0.647 AC: 956 AN: 1478

Alfa AF: 0.743 Hom.: 6123

Bravo AF: 0.667

Asia WGS AF: 0.598 AC: 1510 AN: 2521

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3215593; hg19: chrX-135252234; COSMIC: COSV107443878;