rs368428875

chrX-136209862-TC-TchrX-136209862-TC-TCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001159702.3(FHL1):c.889-3del variant causes a splice region, splice polypyrimidine tract, 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_001159702.3 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.111

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 198465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136209862-TC-T is described in Lovd as [Likely_benign]. Variant chrX-136209862-TC-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159699.2	c.737-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370683.6
FHL1	NM_001159702.3	c.889-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000370683.6	c.737-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001159699.2	P1
FHL1	ENST00000394155.8	c.889-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001159702.3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 160 AN: 109147 Hom.: 0 Cov.: 20 AF XY: 0.00101 AC XY: 32 AN XY: 31665

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

GnomAD3 exomes AF: 0.00130 AC: 219 AN: 168269 Hom.: 1 AF XY: 0.000498 AC XY: 29 AN XY: 58243

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 SAS exome AF: 0.000638

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

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.000161

Gnomad4 EAS exome AF: 0.000208

Gnomad4 SAS exome AF: 0.000486

Gnomad4 FIN exome AF: 0.000391

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.000654

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

Gnomad4 AFR AF: 0.00432

Gnomad4 AMR AF: 0.000878

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000287

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000178

Gnomad4 NFE AF: 0.000344

Gnomad4 OTH AF: 0.00134

Alfa AF: 0.000784 Hom.: 2

Bravo AF: 0.00179

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 13, 2020	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2016	- -

X-linked myopathy with postural muscle atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs368428875; hg19: chrX-135292021;