Variant X-136147631-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001159702.3(FHL1):c.-101+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000057 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

FHL1
NM_001159702.3 splice_donor_region, intron

Scores

Splicing: ADA: 0.7297

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.133

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000573 (6/104723) while in subpopulation AMR AF= 0.000296 (3/10142). AF 95% confidence interval is 0.00008. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3 linkuse as main transcript	c.-101+3A>G		splice_donor_region_variant, intron_variant		ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 linkuse as main transcript	c.-101+3A>G		splice_donor_region_variant, intron_variant		5	NM_001159702.3	ENSP00000377710		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0000573

AC:

AN:

104684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28696

show subpopulations

Gnomad AFR

AF:

0.0000351

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000296

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:

0.0000394

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

154

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 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000573

AC:

AN:

104723

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28743

show subpopulations

Gnomad4 AFR

AF:

0.0000350

Gnomad4 AMR

AF:

0.000296

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000394

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Uruguay Faciocardiomusculoskeletal syndrome;C2678055:X-linked myopathy with postural muscle atrophy;C2678061:X-linked scapuloperoneal muscular dystrophy;C4225159:Myopathy, reducing body, X-linked, childhood-onset;C4225423:Myopathy, reducing body, X-linked, early-onset, severe

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 26, 2018

The c.-101+3 A>G variant has not been published as pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.-101+3 A>G variant is located in intron 1, in the 5' UTR. Several splice prediction algorithms predict that the c.-101+3 A>G variant may damage or destroy the natural splice donor site in intron 1, leading to abnormal gene splicing. Other splice site variants in the FHL1 gene have been reported in HGMD in association with syndromic and neuromuscular disorders, though no FHL1 splice site variant have been associated with an isolated cardiomyopathy phenotype (Stenson et al., 2014). In the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.73

dbscSNV1_RF

Benign

0.56

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