X-136207050-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001159699.2(FHL1):c.239C>T(p.Thr80Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,993 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T80N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

FHL1
NM_001159699.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.129

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.191C>T	p.Thr64Ile	missense_variant	Exon 4 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2 link	c.239C>T	p.Thr80Ile	missense_variant	Exon 3 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.191C>T	p.Thr64Ile	missense_variant	Exon 4 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2
FHL1	ENST00000370683.6 link	c.239C>T	p.Thr80Ile	missense_variant	Exon 3 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

112012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34214

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183137

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67645

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097981

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363407

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000893

AC:

AN:

112012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34214

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked myopathy with postural muscle atrophy

Uncertain:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 64 of the FHL1 protein (p.Thr64Ile). This variant is present in population databases (rs746834335, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 581366). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.0058

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;D;.;T;.;D;D;T;.;.;T;D;.;T;D;.;.;D;.;D;D;.;.;.;D;D;.

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.55

MetaRNN

Uncertain

0.44

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

MetaSVM

Uncertain

-0.063

MutationAssessor

Uncertain

2.7

M;M;M;.;M;.;.;.;.;M;.;.;M;.;.;M;M;.;.;.;M;.;.;.;.;.;M

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.2

.;N;N;.;.;N;D;.;.;.;.;N;N;.;N;N;N;N;.;D;N;.;N;N;D;N;.

REVEL

Uncertain

0.49

Sift

Benign

0.16

.;T;T;.;.;D;T;.;.;.;.;D;T;.;D;T;T;T;.;T;T;.;T;T;T;D;.

Sift4G

Benign

0.18

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

Polyphen

0.85, 0.16

.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;B;.;.

Vest4

0.38

MutPred

0.53

Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);.;.;.;Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);

MVP

0.76

MPC

1.4

ClinPred

0.58

GERP RS

4.0

Varity_R

0.089

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over