rs367592190

Positions:

chrX-136209314-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The ENST00000370683.6(FHL1):c.737-557C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,208,993 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.000027 ( 0 hom. 8 hem. )

Consequence

FHL1
ENST00000370683.6 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.03

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14491272).

BP6

Variant X-136209314-C-T is Benign according to our data. Variant chrX-136209314-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290191.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000216 (24/111059) while in subpopulation AFR AF= 0.000657 (20/30448). AF 95% confidence interval is 0.000435. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3 linkuse as main transcript	c.760C>T	p.Arg254Cys	missense_variant	7/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2 linkuse as main transcript	c.737-557C>T		intron_variant		ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 linkuse as main transcript	c.760C>T	p.Arg254Cys	missense_variant	7/8	5	NM_001159702.3	ENSP00000377710		Q13642-2
FHL1	ENST00000370683.6 linkuse as main transcript	c.737-557C>T		intron_variant		1	NM_001159699.2	ENSP00000359717	P1	Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

111059

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

AN XY:

33235

show subpopulations

Gnomad AFR

AF:

0.000657

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000755

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000663

AC:

AN:

180955

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

67323

show subpopulations

Gnomad AFR exome

AF:

0.000568

Gnomad AMR exome

AF:

0.000183

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:

0.0000273

AC:

AN:

1097934

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363374

show subpopulations

Gnomad4 AFR exome

AF:

0.000682

Gnomad4 AMR exome

AF:

0.000142

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:

0.00000475

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.000216

AC:

AN:

111059

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

AN XY:

33235

show subpopulations

Gnomad4 AFR

AF:

0.000657

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000755

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000761

AC:

ESP6500EA

AF:

0.000182

AC:

ExAC

AF:

0.0000996

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 01, 2018

- -

X-linked myopathy with postural muscle atrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;T

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.87

D;.

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

0.96

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

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

2.1

N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.32

MVP

0.93

MPC

1.3

ClinPred

0.13

GERP RS

3.9

Varity_R

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

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