Genetic Variant FHL1:p.Thr313Met (chrX-136209920-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001159702.3(FHL1):c.938C>T(p.Thr313Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,208,617 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T313R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., 21 hem., cov: 22)

Exomes 𝑓: 0.000076 ( 0 hom. 23 hem. )

Consequence

FHL1
NM_001159702.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.332

Publications

1 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 7 uncertain in NM_001159702.3

BP4

Computational evidence support a benign effect (MetaRNN=0.011277348).

BP6

Variant X-136209920-C-T is Benign according to our data. Variant chrX-136209920-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000679 (75/110489) while in subpopulation AFR AF = 0.0023 (70/30399). AF 95% confidence interval is 0.00187. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 21 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.938C>T	p.Thr313Met	missense	Exon 8 of 8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2	MANE Select	c.786C>T	p.His262His	synonymous	Exon 6 of 6	NP_001153171.1	Q13642-5
FHL1	NM_001440769.1		c.986C>T	p.Thr329Met	missense	Exon 7 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.938C>T	p.Thr313Met	missense	Exon 8 of 8	ENSP00000377710.2	Q13642-2
FHL1	ENST00000370683.6	TSL:1 MANE Select	c.786C>T	p.His262His	synonymous	Exon 6 of 6	ENSP00000359717.1	Q13642-5
FHL1	ENST00000543669.5	TSL:1	c.738C>T	p.His246His	synonymous	Exon 6 of 6	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes

AF:

0.000679

AC:

AN:

110440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00231

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000193

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:

0.0000378

Gnomad OTH

AF:

0.000679

GnomAD2 exomes

AF:

0.000207

AC:

AN:

183470

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00243

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000756

AC:

AN:

1098128

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363488

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

26401

American (AMR)

AF:

0.0000852

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000993

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4103

European-Non Finnish (NFE)

AF:

0.00000831

AC:

AN:

842063

Other (OTH)

AF:

0.000108

AC:

AN:

46088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000679

AC:

AN:

110489

Hom.:

Cov.:

AF XY:

0.000642

AC XY:

AN XY:

32731

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

30399

American (AMR)

AF:

0.000193

AC:

AN:

10372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3511

South Asian (SAS)

AF:

0.00

AC:

AN:

2531

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5781

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52868

Other (OTH)

AF:

0.000671

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000253

Hom.:

Bravo

AF:

0.000835

ESP6500AA

AF:

0.00261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (2)

Cardiovascular phenotype (1)

FHL1-related disorder (1)

X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

PhyloP100

0.33

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.030

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Benign

0.26

Polyphen

0.13

Vest4

0.14

MVP

0.73

MPC

1.4

ClinPred

0.11

GERP RS

4.6

Varity_R

0.17

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over