rs747922027

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001159699.2(FHL1):c.856C>G(p.Gln286Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,982 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

FHL1
NM_001159699.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.31

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

X-linked myopathy with postural muscle atrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
myopathy, reducing body, X-linked, early-onset, severe
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
reducing body myopathy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Emery-Dreifuss muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked scapuloperoneal muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

FHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_001159699.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13909888).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159699.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FHL1	NM_001159699.2	MANE Select	c.856C>G	p.Gln286Glu	missense	Exon 6 of 6	NP_001153171.1
FHL1	NM_001159702.3	MANE Plus Clinical	c.*36C>G		3_prime_UTR	Exon 8 of 8	NP_001153174.1
FHL1	NM_001159701.2		c.895C>G	p.Gln299Glu	missense	Exon 6 of 6	NP_001153173.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FHL1	ENST00000370683.6	TSL:1 MANE Select	c.856C>G	p.Gln286Glu	missense	Exon 6 of 6	ENSP00000359717.1
FHL1	ENST00000543669.5	TSL:1	c.808C>G	p.Gln270Glu	missense	Exon 6 of 6	ENSP00000443333.1
FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.*36C>G		3_prime_UTR	Exon 8 of 8	ENSP00000377710.2

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000659

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183530

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

9.11e-7

AC:

AN:

1098208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363562

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842098

Other (OTH)

AF:

0.00

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32978

show subpopulations

African (AFR)

AF:

0.0000659

AC:

AN:

30362

American (AMR)

AF:

0.00

AC:

AN:

10412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2587

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5859

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52948

Other (OTH)

AF:

0.00

AC:

AN:

1489

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.84

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.75

M_CAP

Benign

0.061

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.46

PhyloP100

1.3

PROVEAN

Benign

0.40

REVEL

Benign

0.26

Sift

Benign

0.63

Sift4G

Benign

0.32

Vest4

0.34

MutPred

0.48

Loss of helix (P = 0.028)

MVP

0.77

ClinPred

0.096

GERP RS

4.7

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over