X-136206125-A-G

Variant names:

• chrX-136206125-A-G
• rs17001989
• NM_001159702.3:c.-26-282A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001159699.2(FHL1):​c.23-282A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 411,915 control chromosomes in the GnomAD database, including 71 homozygotes. There are 891 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (51 hom., 669 hem., cov: 23)
  • Exomes 𝑓: 0.0031 (20 hom. 222 hem.)
• Consequence: FHL1 NM_001159699.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.133
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-136206125-A-G is Benign according to our data. Variant chrX-136206125-A-G is described in ClinVar as [Benign]. Clinvar id is 669527.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-26-282A>G		intron_variant	Intron 2 of 7	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.23-282A>G		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.-26-282A>G		intron_variant	Intron 2 of 7	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.23-282A>G		intron_variant	Intron 1 of 5	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 2348 AN: 112818 Hom.: 51 Cov.: 23

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.00306 AC: 916 AN: 299045 Hom.: 20 Cov.: 0 AF XY: 0.00231 AC XY: 222 AN XY: 96099

African (AFR) AF: 0.0711 AC: 646 AN: 9088

American (AMR) AF: 0.00810 AC: 109 AN: 13455

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9119

East Asian (EAS) AF: 0.00 AC: 0 AN: 20883

South Asian (SAS) AF: 0.0000749 AC: 2 AN: 26706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19789

Middle Eastern (MID) AF: 0.00321 AC: 4 AN: 1245

European-Non Finnish (NFE) AF: 0.000133 AC: 24 AN: 180706

Other (OTH) AF: 0.00726 AC: 131 AN: 18054

GnomAD4 genome AF: 0.0208 AC: 2348 AN: 112870 Hom.: 51 Cov.: 23 AF XY: 0.0191 AC XY: 669 AN XY: 35032

African (AFR) AF: 0.0693 AC: 2154 AN: 31071

American (AMR) AF: 0.0146 AC: 158 AN: 10788

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6281

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53316

Other (OTH) AF: 0.0175 AC: 27 AN: 1541

Alfa AF: 0.0169 Hom.: 58

Bravo AF: 0.0241

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.7
DANN	Benign	0.67
PhyloP100		0.13
PromoterAI		0.10	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17001989; hg19: chrX-135288284;