rs182106777

Positions:

chrX-136206593-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001159702.3(FHL1):c.156+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000997 in 1,211,187 control chromosomes in the GnomAD database, including 7 homozygotes. There are 329 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 2 hom., 157 hem., cov: 24)

Exomes 𝑓: 0.00058 ( 5 hom. 172 hem. )

Consequence

FHL1
NM_001159702.3 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.0002034

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.09

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-136206593-C-T is Benign according to our data. Variant chrX-136206593-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136206593-C-T is described in Lovd as [Benign]. Variant chrX-136206593-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00505 (571/113093) while in subpopulation AFR AF= 0.0172 (537/31201). AF 95% confidence interval is 0.016. There are 2 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159699.2 linkuse as main transcript	c.204+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000370683.6
FHL1	NM_001159702.3 linkuse as main transcript	c.156+5C>T		splice_donor_5th_base_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.204+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_001159699.2	P1	Q13642-5
FHL1	ENST00000394155.8 linkuse as main transcript	c.156+5C>T		splice_donor_5th_base_variant, intron_variant		5	NM_001159702.3		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

568

AN:

113042

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

154

AN XY:

35192

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00653

GnomAD3 exomes

AF:

0.00150

AC:

276

AN:

183425

Hom.:

AF XY:

0.000855

AC XY:

AN XY:

67863

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.000802

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000579

AC:

636

AN:

1098094

Hom.:

Cov.:

AF XY:

0.000473

AC XY:

172

AN XY:

363448

show subpopulations

Gnomad4 AFR exome

AF:

0.0180

Gnomad4 AMR exome

AF:

0.000852

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000629

Gnomad4 OTH exome

AF:

0.00150

GnomAD4 genome

AF:

0.00505

AC:

571

AN:

113093

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

157

AN XY:

35253

show subpopulations

Gnomad4 AFR

AF:

0.0172

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00645

Alfa

AF:

0.00295

Hom.:

Bravo

AF:

0.00545

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 29, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2019	- -

X-linked myopathy with postural muscle atrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Familial hemophagocytic lymphohistiocytosis type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 21, 2022

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2019

This alteration is classified as 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

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.16

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.0020

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

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