rs368428875

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.111

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159699.2 linkuse as main transcript	c.737-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370683.6
FHL1	NM_001159702.3 linkuse as main transcript	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 linkuse as main transcript	c.737-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001159699.2	P1	Q13642-5
FHL1	ENST00000394155.8 linkuse as main transcript	c.889-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001159702.3		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

160

AN:

109147

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

31665

show subpopulations

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.:

AF XY:

0.000498

AC XY:

AN XY:

58243

show subpopulations

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.:

Cov.:

AF XY:

0.000398

AC XY:

135

AN XY:

339267

show subpopulations

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.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

31721

show subpopulations

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.:

Bravo

AF:

0.00179

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 13, 2020	- -

not provided

Benign:2

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

X-linked myopathy with postural muscle atrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over