rs754404850

Variant names:

• chrX-136209859-TTTTC-T
• rs754404850
• NM_001159702.3:c.889-11_889-8delTTTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000370683.6(FHL1):​c.737-11_737-8delTTTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,202,652 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 3 hem., cov: 20)
  • Exomes 𝑓: 0.00012 (0 hom. 43 hem.)
• Consequence: FHL1 ENST00000370683.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.61
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant X-136209859-TTTTC-T is Benign according to our data. Variant chrX-136209859-TTTTC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 537361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000109 (12/110211) while in subpopulation EAS AF = 0.000285 (1/3506). AF 95% confidence interval is 0.000089. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370683.6. 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.889-11_889-8delTTTC		splice_region intron	N/A	NP_001153174.1
	FHL1	NM_001159699.2	MANE Select	c.737-11_737-8delTTTC		splice_region intron	N/A	NP_001153171.1
	FHL1	NM_001440769.1		c.937-11_937-8delTTTC		splice_region intron	N/A	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.889-11_889-8delTTTC		splice_region intron	N/A	ENSP00000377710.2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.737-11_737-8delTTTC		splice_region intron	N/A	ENSP00000359717.1
	FHL1	ENST00000543669.5	TSL:1	c.689-11_689-8delTTTC		splice_region intron	N/A	ENSP00000443333.1

Frequencies

GnomAD3 genomes AF: 0.000109 AC: 12 AN: 110159 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000662

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000171

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000832 AC: 15 AN: 180310 AF XY: 0.000168

Gnomad AFR exome AF: 0.0000770

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: 0.0000873

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 130 AN: 1092441 Hom.: 0 AF XY: 0.000119 AC XY: 43 AN XY: 360647

African (AFR) AF: 0.000228 AC: 6 AN: 26288

American (AMR) AF: 0.0000286 AC: 1 AN: 34921

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19346

East Asian (EAS) AF: 0.0000994 AC: 3 AN: 30191

South Asian (SAS) AF: 0.000482 AC: 26 AN: 53917

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3591

European-Non Finnish (NFE) AF: 0.000104 AC: 87 AN: 838022

Other (OTH) AF: 0.000109 AC: 5 AN: 45825

GnomAD4 genome AF: 0.000109 AC: 12 AN: 110211 Hom.: 0 Cov.: 20 AF XY: 0.0000923 AC XY: 3 AN XY: 32507

African (AFR) AF: 0.0000661 AC: 2 AN: 30261

American (AMR) AF: 0.00 AC: 0 AN: 10354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3506

South Asian (SAS) AF: 0.00 AC: 0 AN: 2535

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000171 AC: 9 AN: 52750

Other (OTH) AF: 0.00 AC: 0 AN: 1499

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
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: rs754404850; hg19: chrX-135292018;