Genetic Variant NM_001159702.3:c.450C>T (chrX-136207910-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001159702.3(FHL1):c.450C>T(p.Cys150Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00079 in 1,210,957 control chromosomes in the GnomAD database, including 3 homozygotes. There are 330 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 39 hem., cov: 23)

Exomes 𝑓: 0.00075 ( 3 hom. 291 hem. )

Consequence

FHL1
NM_001159702.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0320

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant X-136207910-C-T is Benign according to our data. Variant chrX-136207910-C-T is described in ClinVar as Benign. ClinVar VariationId is 284513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.032 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00119 (134/112834) while in subpopulation EAS AF = 0.0169 (60/3559). AF 95% confidence interval is 0.0134. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 39 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159702.3. 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.450C>T	p.Cys150Cys	synonymous	Exon 5 of 8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2	MANE Select	c.498C>T	p.Cys166Cys	synonymous	Exon 4 of 6	NP_001153171.1	Q13642-5
FHL1	NM_001440769.1		c.498C>T	p.Cys166Cys	synonymous	Exon 4 of 7	NP_001427698.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.450C>T	p.Cys150Cys	synonymous	Exon 5 of 8	ENSP00000377710.2	Q13642-2
FHL1	ENST00000370683.6	TSL:1 MANE Select	c.498C>T	p.Cys166Cys	synonymous	Exon 4 of 6	ENSP00000359717.1	Q13642-5
FHL1	ENST00000543669.5	TSL:1	c.450C>T	p.Cys150Cys	synonymous	Exon 4 of 6	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

135

AN:

112782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000558

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0171

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000657

GnomAD2 exomes

AF:

0.00177

AC:

325

AN:

183403

AF XY:

0.00178

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0170

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000749

AC:

823

AN:

1098123

Hom.:

Cov.:

AF XY:

0.000801

AC XY:

291

AN XY:

363479

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

26398

American (AMR)

AF:

0.000256

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19384

East Asian (EAS)

AF:

0.0142

AC:

429

AN:

30206

South Asian (SAS)

AF:

0.00151

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000247

AC:

208

AN:

842030

Other (OTH)

AF:

0.00106

AC:

AN:

46090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00119

AC:

134

AN:

112834

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

35000

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

31144

American (AMR)

AF:

0.000557

AC:

AN:

10774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.0169

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2735

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

53316

Other (OTH)

AF:

0.000649

AC:

AN:

1540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000618

Hom.:

Bravo

AF:

0.00154

EpiCase

AF:

0.000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Cardiovascular phenotype (1)

FHL1-related disorder (1)

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

-0.41

CADD

Benign

6.6

(source)

DANN

Benign

0.58

PhyloP100

0.032

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over