X-136147571-C-G

Variant names:

• chrX-136147571-C-G
• rs777858178
• NM_001159702.3:c.-158C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001159702.3(FHL1):​c.-158C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000093 (0 hom., 0 hem., cov: 20)
• Consequence: FHL1 NM_001159702.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.233
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• X-linked myopathy with postural muscle atrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myopathy, reducing body, X-linked, early-onset, severe

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• reducing body myopathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked scapuloperoneal muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-158C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159702.3	c.-158C>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-158C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000394155.8	c.-158C>G		5_prime_UTR_variant	Exon 1 of 8	5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes AF: 0.00000926 AC: 1 AN: 108014 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

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: 0.0000194

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00000925 AC: 1 AN: 108055 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 31237

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29962

American (AMR) AF: 0.00 AC: 0 AN: 10463

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2603

East Asian (EAS) AF: 0.00 AC: 0 AN: 3327

South Asian (SAS) AF: 0.00 AC: 0 AN: 2531

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5303

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 209

European-Non Finnish (NFE) AF: 0.0000194 AC: 1 AN: 51543

Other (OTH) AF: 0.00 AC: 0 AN: 1469

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.89
PhyloP100		-0.23
PromoterAI		-0.0010	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777858178; hg19: chrX-135229730;