X-136206155-C-A

Variant names:

• chrX-136206155-C-A
• rs17284031
• NM_001159702.3:c.-26-252C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS1

The NM_001159702.3(FHL1):​c.-26-252C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000068 in 441,375 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000061 (0 hom. 0 hem.)
• Consequence: FHL1 NM_001159702.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.692
• 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 -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000609 (2/328534) while in subpopulation AFR AF = 0.000203 (2/9870). AF 95% confidence interval is 0.0000354. There are 0 homozygotes in GnomAdExome4. There are 0 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-26-252C>A		intron_variant	Intron 2 of 7	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.23-252C>A		intron_variant	Intron 1 of 5	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-26-252C>A		intron_variant	Intron 2 of 7	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.23-252C>A		intron_variant	Intron 1 of 5	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes AF: 0.00000886 AC: 1 AN: 112841 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000322

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000609 AC: 2 AN: 328534 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 112260

African (AFR) AF: 0.000203 AC: 2 AN: 9870

American (AMR) AF: 0.00 AC: 0 AN: 15793

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10056

East Asian (EAS) AF: 0.00 AC: 0 AN: 22947

South Asian (SAS) AF: 0.00 AC: 0 AN: 28161

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1379

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 198744

Other (OTH) AF: 0.00 AC: 0 AN: 19698

GnomAD4 genome AF: 0.00000886 AC: 1 AN: 112841 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34979

African (AFR) AF: 0.0000322 AC: 1 AN: 31074

American (AMR) AF: 0.00 AC: 0 AN: 10762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2743

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6283

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53296

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.00 Hom.: 97

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.32
DANN	Benign	0.77
PhyloP100		-0.69
PromoterAI		-0.025	Neutral

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

Other links and lift over

dbSNP: rs17284031; hg19: chrX-135288314;