Variant X-136196863-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP6_ModerateBS1BS2

The NM_001159702.3(FHL1):c.-26-9544G>T variant causes a intron change. The variant allele was found at a frequency of 0.0000146 in 1,163,229 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000076 ( 0 hom. 2 hem. )

Consequence

FHL1
NM_001159702.3 intron

Scores

Splicing: ADA: 0.9897

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.34

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant X-136196863-G-T is Benign according to our data. Variant chrX-136196863-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3036058.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000808 (9/111433) while in subpopulation AMR AF= 0.000286 (3/10488). AF 95% confidence interval is 0.0000774. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3 linkuse as main transcript	c.-26-9544G>T		intron_variant		ENST00000394155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8 linkuse as main transcript	c.-26-9544G>T		intron_variant		5	NM_001159702.3		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0000808

AC:

AN:

111433

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33635

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

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:

0.00

Gnomad OTH

AF:

0.000669

GnomAD3 exomes

AF:

0.0000530

AC:

AN:

113237

Hom.:

AF XY:

0.0000495

AC XY:

AN XY:

40405

show subpopulations

Gnomad AFR exome

AF:

0.000780

Gnomad AMR exome

AF:

0.0000515

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000761

AC:

AN:

1051796

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

342760

show subpopulations

Gnomad4 AFR exome

AF:

0.000201

Gnomad4 AMR exome

AF:

0.0000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000122

Gnomad4 OTH exome

AF:

0.0000226

GnomAD4 genome

AF:

0.0000808

AC:

AN:

111433

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33635

show subpopulations

Gnomad4 AFR

AF:

0.000163

Gnomad4 AMR

AF:

0.000286

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000669

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000204

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

FHL1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.45

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.67

MutPred

0.58

Loss of disorder (P = 0.0062);

MVP

0.78

ClinPred

0.20

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.88

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