chrX-136196860-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001159702.3(FHL1):​c.-26-9547G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,163,238 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 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 0.00035 ( 0 hom., 18 hem., cov: 23)
Exomes 𝑓: 0.00016 ( 0 hom. 48 hem. )

Consequence

FHL1
NM_001159702.3 intron

Scores

1
12

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.10
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008448601).
BP6
Variant X-136196860-G-A is Benign according to our data. Variant chrX-136196860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 993975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00035 (39/111409) while in subpopulation AMR AF= 0.00171 (18/10496). AF 95% confidence interval is 0.00111. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FHL1NM_001159702.3 linkuse as main transcriptc.-26-9547G>A 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.-26-9547G>A intron_variant 5 NM_001159702.3 ENSP00000377710 Q13642-2

Frequencies

GnomAD3 genomes
AF:
0.000350
AC:
39
AN:
111355
Hom.:
0
Cov.:
23
AF XY:
0.000536
AC XY:
18
AN XY:
33569
show subpopulations
Gnomad AFR
AF:
0.000686
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00172
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:
0.000990
AC:
112
AN:
113170
Hom.:
0
AF XY:
0.000693
AC XY:
28
AN XY:
40404
show subpopulations
Gnomad AFR exome
AF:
0.000469
Gnomad AMR exome
AF:
0.00561
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:
0.000162
AC:
170
AN:
1051829
Hom.:
0
Cov.:
29
AF XY:
0.000140
AC XY:
48
AN XY:
342801
show subpopulations
Gnomad4 AFR exome
AF:
0.000603
Gnomad4 AMR exome
AF:
0.00463
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000201
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000269
Gnomad4 OTH exome
AF:
0.0000677
GnomAD4 genome
AF:
0.000350
AC:
39
AN:
111409
Hom.:
0
Cov.:
23
AF XY:
0.000535
AC XY:
18
AN XY:
33633
show subpopulations
Gnomad4 AFR
AF:
0.000684
Gnomad4 AMR
AF:
0.00171
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
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000774
ExAC
AF:
0.0000655
AC:
3

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 27, 2021- -
FHL1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 02, 2020This variant is classified as 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
-0.76
T
BayesDel_noAF
Benign
-0.87
CADD
Benign
9.8
DANN
Benign
0.77
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.30
T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.0084
T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.98
D;D;D;D;D;D;D;N
PROVEAN
Benign
0.070
N
REVEL
Benign
0.080
Sift
Benign
0.54
T
Sift4G
Benign
0.63
T
Vest4
0.12
MVP
0.43
ClinPred
0.0024
T
GERP RS
-4.1

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.

Other links and lift over

dbSNP: rs192893870; hg19: chrX-135279019; COSMIC: COSV61782755; COSMIC: COSV61782755; API