X-136147631-A-G

Variant names:

• chrX-136147631-A-G
• rs895540444
• NM_001159702.3:c.-101+3A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001159702.3(FHL1):​c.-101+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.7297
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.133

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]

ACMG classification

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 rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-101+3A>G		splice_region_variant, intron_variant	Intron 1 of 7	ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-101+3A>G		splice_region_variant, intron_variant	Intron 1 of 7	5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes AF: 0.0000573 AC: 6 AN: 104684 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 28696

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: 0 AN: 662 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 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: 6 AN: 104723 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 28743

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

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

Jul 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 26, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	21
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

Other links and lift over

dbSNP: rs895540444; hg19: chrX-135229790;