chrX-136196863-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_001159702.3(FHL1):​c.-26-9544G>T variant causes a intron 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. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.0000076 ( 0 hom. 2 hem. )

Consequence

FHL1
NM_001159702.3 intron

Scores

4
2
7
Splicing: ADA: 0.9897
2

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.34
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3
Splicing scoreres supports a deletorius 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 id 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FHL1NM_001159702.3 linkuse as main transcriptc.-26-9544G>T intron_variant ENST00000394155.8 NP_001153174.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FHL1ENST00000394155.8 linkuse as main transcriptc.-26-9544G>T intron_variant 5 NM_001159702.3 ENSP00000377710 Q13642-2

Frequencies

GnomAD3 genomes
AF:
0.0000808
AC:
9
AN:
111433
Hom.:
0
Cov.:
23
AF XY:
0.0000297
AC XY:
1
AN XY:
33635
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
GnomAD3 exomes
AF:
0.0000530
AC:
6
AN:
113237
Hom.:
0
AF XY:
0.0000495
AC XY:
2
AN XY:
40405
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 SAS 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:
8
AN:
1051796
Hom.:
0
Cov.:
29
AF XY:
0.00000583
AC XY:
2
AN XY:
342760
show subpopulations
Gnomad4 AFR exome
AF:
0.000201
Gnomad4 AMR exome
AF:
0.0000358
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:
0.00000122
Gnomad4 OTH exome
AF:
0.0000226
GnomAD4 genome
AF:
0.0000808
AC:
9
AN:
111433
Hom.:
0
Cov.:
23
AF XY:
0.0000297
AC XY:
1
AN XY:
33635
show subpopulations
Gnomad4 AFR
AF:
0.000163
Gnomad4 AMR
AF:
0.000286
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:
0.000669
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000204
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

FHL1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 31, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
22
DANN
Uncertain
1.0
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.46
T
M_CAP
Pathogenic
0.49
D
MetaRNN
Uncertain
0.62
D
MetaSVM
Benign
-0.45
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.21
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.67
MutPred
0.58
Loss of disorder (P = 0.0062);
MVP
0.78
ClinPred
0.20
T
GERP RS
5.8

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

LitVar

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

Other links and lift over

dbSNP: rs774418125; hg19: chrX-135279022; API