dbSNP rs774418125: FHL1:c.-26-9544G>T (chrX-136196863-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_001159701.2(FHL1):c.61G>T(p.Gly21Cys) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21V) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000076 ( 0 hom. 2 hem. )

Consequence

FHL1
NM_001159701.2 missense, splice_region

Scores

Splicing: ADA: 0.9897

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.34

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), G2P, Orphanet
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 -8 ACMG points.

PP3

Splicing predictors support a deleterious 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 VariationId is 3036058.Status of the report is no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159701.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FHL1	NM_001159702.3	MANE Plus Clinical	c.-26-9544G>T		intron	N/A	NP_001153174.1	Q13642-2
FHL1	NM_001159701.2		c.61G>T	p.Gly21Cys	missense splice_region	Exon 1 of 6	NP_001153173.1	Q13642-4
FHL1	NM_001369326.1		c.-26-9544G>T		intron	N/A	NP_001356255.1	Q13642-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.-26-9544G>T		intron	N/A	ENSP00000377710.2	Q13642-2
FHL1	ENST00000543669.5	TSL:1	c.-26-9544G>T		intron	N/A	ENSP00000443333.1	Q13642-1
FHL1	ENST00000539015.5	TSL:2	c.61G>T	p.Gly21Cys	missense splice_region	Exon 1 of 6	ENSP00000437673.1	Q13642-4

Frequencies

GnomAD3 genomes

AF:

0.0000808

AC:

AN:

111433

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000530

AC:

AN:

113237

AF XY:

0.0000495

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000201

AC:

AN:

24870

American (AMR)

AF:

0.0000358

AC:

AN:

27895

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18623

East Asian (EAS)

AF:

0.00

AC:

AN:

27126

South Asian (SAS)

AF:

0.00

AC:

AN:

49758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37609

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3877

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

817744

Other (OTH)

AF:

0.0000226

AC:

AN:

44294

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000105225), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

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:

0.0000808

AC:

AN:

111433

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33635

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

30622

American (AMR)

AF:

0.000286

AC:

AN:

10488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5979

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53123

Other (OTH)

AF:

0.000669

AC:

AN:

1495

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000434

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000204

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

FHL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

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

PhyloP100

6.3

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

PromoterAI

0.039

Neutral

(source)

Mutation Taster

=227/73

polymorphism

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over