rs368428875

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-136209862-TC-T
• chrX-136209862-TC-TCC

Variant summary

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

The NM_001159699.2(FHL1):​c.737-3delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,162,380 control chromosomes in the GnomAD database, including 1 homozygotes. There are 168 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 0.0015 (0 hom., 33 hem., cov: 20)
  • Exomes 𝑓: 0.00057 (1 hom. 135 hem.)
• Consequence: FHL1 NM_001159699.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant X-136209862-TC-T is Benign according to our data. Variant chrX-136209862-TC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00147 (161/109191) while in subpopulation AFR AF = 0.00432 (130/30082). AF 95% confidence interval is 0.00372. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 33 XL gene

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.889-3delC		splice_region intron	N/A	NP_001153174.1
	FHL1	NM_001159699.2	MANE Select	c.737-3delC		splice_region intron	N/A	NP_001153171.1
	FHL1	NM_001440769.1		c.937-3delC		splice_region 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.889-8delC		splice_region intron	N/A	ENSP00000377710.2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.737-8delC		splice_region intron	N/A	ENSP00000359717.1
	FHL1	ENST00000543669.5	TSL:1	c.689-8delC		splice_region intron	N/A	ENSP00000443333.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 160 AN: 109147 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000879

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000286

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000344

Gnomad OTH AF: 0.00136

GnomAD2 exomes AF: 0.00130 AC: 219 AN: 168269 AF XY: 0.000498

Gnomad AFR exome AF: 0.00484

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.000573

Gnomad EAS exome AF: 0.00113

Gnomad FIN exome AF: 0.000401

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.000572 AC: 602 AN: 1053189 Hom.: 1 Cov.: 32 AF XY: 0.000398 AC XY: 135 AN XY: 339267

African (AFR) AF: 0.00526 AC: 135 AN: 25650

American (AMR) AF: 0.00111 AC: 37 AN: 33342

Ashkenazi Jewish (ASJ) AF: 0.000161 AC: 3 AN: 18665

East Asian (EAS) AF: 0.000208 AC: 6 AN: 28848

South Asian (SAS) AF: 0.000486 AC: 25 AN: 51398

European-Finnish (FIN) AF: 0.000391 AC: 15 AN: 38367

Middle Eastern (MID) AF: 0.00113 AC: 4 AN: 3553

European-Non Finnish (NFE) AF: 0.000430 AC: 348 AN: 809051

Other (OTH) AF: 0.000654 AC: 29 AN: 44315

GnomAD4 genome AF: 0.00147 AC: 161 AN: 109191 Hom.: 0 Cov.: 20 AF XY: 0.00104 AC XY: 33 AN XY: 31721

African (AFR) AF: 0.00432 AC: 130 AN: 30082

American (AMR) AF: 0.000878 AC: 9 AN: 10249

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

East Asian (EAS) AF: 0.000287 AC: 1 AN: 3480

South Asian (SAS) AF: 0.00 AC: 0 AN: 2462

European-Finnish (FIN) AF: 0.000178 AC: 1 AN: 5607

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000344 AC: 18 AN: 52312

Other (OTH) AF: 0.00134 AC: 2 AN: 1488

Alfa AF: 0.000784 Hom.: 2

Bravo AF: 0.00179

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	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)		0.010		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; COSMIC: COSV61783125; COSMIC: COSV61783125;