rs768705041

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_001159702.3(FHL1):c.961A>G(p.Asn321Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,208,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N321N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000022 ( 0 hom. 11 hem. )

Consequence

FHL1
NM_001159702.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.85

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: Benign. The variant received -9 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 8 uncertain in NM_001159702.3

BP4

Computational evidence support a benign effect (MetaRNN=0.082158655).

BP6

Variant X-136209943-A-G is Benign according to our data. Variant chrX-136209943-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469631.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000271 (3/110580) while in subpopulation EAS AF = 0.00085 (3/3529). AF 95% confidence interval is 0.000231. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.961A>G	p.Asn321Asp	missense_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2 link	c.809A>G	p.Lys270Arg	missense_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1	Q13642-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 link	c.961A>G	p.Asn321Asp	missense_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2
FHL1	ENST00000370683.6 link	c.809A>G	p.Lys270Arg	missense_variant	Exon 6 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000847

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:

0.0000981

AC:

AN:

183524

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00123

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1098223

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363577

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000530

AC:

AN:

30206

South Asian (SAS)

AF:

0.000129

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842113

Other (OTH)

AF:

0.0000217

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000271

AC:

AN:

110580

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

32814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30410

American (AMR)

AF:

0.00

AC:

AN:

10391

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.000850

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2545

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5821

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52849

Other (OTH)

AF:

0.00

AC:

AN:

1499

Age Distribution

Genome Hom

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:

0.0000341

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Mar 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K254R variant (also known as c.761A>G), located in coding exon 5 of the FHL1 gene, results from an A to G substitution at nucleotide position 761. The lysine at codon 254 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

X-linked myopathy with postural muscle atrophy

Benign:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;.;.;.;.;.;.;.;T;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

.;.;.;.;.;D;D;D;D;.

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.082

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.73

PhyloP100

5.9

PROVEAN

Benign

-0.40

.;N;.;N;N;N;N;N;N;.

REVEL

Benign

0.27

Sift

Benign

0.43

.;T;.;T;T;T;T;T;T;.

Sift4G

Benign

0.36

T;T;T;T;T;T;T;T;T;T

Vest4

0.29

MutPred

0.43

.;.;.;.;.;.;Loss of methylation at K283 (P = 0.0248);.;.;.;

MVP

0.93

ClinPred

0.17

GERP RS

5.6

Varity_R

0.41

Mutation Taster

=94/6

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over