dbSNP rs914754937: FHL1:c.889-9T>C (chrX-136209862-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001159699.2(FHL1):c.737-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,170,211 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 72 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 7 hem., cov: 21)

Exomes 𝑓: 0.00017 ( 0 hom. 65 hem. )

Consequence

FHL1
NM_001159699.2 intron

Scores

Splicing: ADA: 0.00008933

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.586

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant X-136209862-T-C is Benign according to our data. Variant chrX-136209862-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 391549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000192 (21/109207) while in subpopulation EAS AF = 0.000575 (2/3480). AF 95% confidence interval is 0.000255. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

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	Effect	Exon Rank	Protein	UniProt
FHL1	NM_001159702.3	MANE Plus Clinical	c.889-9T>C	intron	N/A	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2	MANE Select	c.737-9T>C	intron	N/A	NP_001153171.1	Q13642-5
FHL1	NM_001440769.1		c.937-9T>C	intron	N/A	NP_001427698.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.889-9T>C	intron	N/A	ENSP00000377710.2	Q13642-2
FHL1	ENST00000370683.6	TSL:1 MANE Select	c.737-9T>C	intron	N/A	ENSP00000359717.1	Q13642-5
FHL1	ENST00000543669.5	TSL:1	c.689-9T>C	intron	N/A	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes

AF:

0.000192

AC:

AN:

109163

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000977

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000573

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000955

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000166

AC:

AN:

168269

AF XY:

0.000223

show subpopulations

Gnomad AFR exome

AF:

0.000318

Gnomad AMR exome

AF:

0.000316

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000172

AC:

183

AN:

1061004

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

344356

show subpopulations

African (AFR)

AF:

0.000349

AC:

AN:

25756

American (AMR)

AF:

0.000267

AC:

AN:

33687

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18802

East Asian (EAS)

AF:

0.000172

AC:

AN:

29087

South Asian (SAS)

AF:

0.000250

AC:

AN:

51990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38765

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3581

European-Non Finnish (NFE)

AF:

0.000176

AC:

143

AN:

814756

Other (OTH)

AF:

0.0000897

AC:

AN:

44580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000192

AC:

AN:

109207

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

AN XY:

31737

show subpopulations

African (AFR)

AF:

0.000432

AC:

AN:

30082

American (AMR)

AF:

0.0000976

AC:

AN:

10250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2624

East Asian (EAS)

AF:

0.000575

AC:

AN:

3480

South Asian (SAS)

AF:

0.00

AC:

AN:

2461

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5613

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000956

AC:

AN:

52322

Other (OTH)

AF:

0.00

AC:

AN:

1488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000427

Hom.:

Bravo

AF:

0.000166

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.82

(source)

DANN

Benign

0.12

PhyloP100

0.59

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000089

dbscSNV1_RF

Benign

0.032

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

Computational scores

Splicing

Publications

Other links and lift over