X-136206155-C-T

Variant names:

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

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.23-252C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 441,390 control chromosomes in the GnomAD database, including 299 homozygotes. There are 5,340 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (84 hom., 1301 hem., cov: 24)
  • Exomes 𝑓: 0.038 (215 hom. 4039 hem.)
• Consequence: FHL1 NM_001159699.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-136206155-C-T is Benign according to our data. Variant chrX-136206155-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1187282.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-26-252C>T		intron_variant	Intron 2 of 7	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.23-252C>T		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>T		intron_variant	Intron 2 of 7	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.23-252C>T		intron_variant	Intron 1 of 5	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 4671 AN: 112833 Hom.: 84 Cov.: 24

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0840

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0566

GnomAD4 exome AF: 0.0377 AC: 12383 AN: 328505 Hom.: 215 Cov.: 0 AF XY: 0.0360 AC XY: 4039 AN XY: 112259

African (AFR) AF: 0.0442 AC: 436 AN: 9870

American (AMR) AF: 0.0329 AC: 520 AN: 15793

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 690 AN: 10054

East Asian (EAS) AF: 0.0000436 AC: 1 AN: 22947

South Asian (SAS) AF: 0.0102 AC: 288 AN: 28161

European-Finnish (FIN) AF: 0.0244 AC: 534 AN: 21882

Middle Eastern (MID) AF: 0.0754 AC: 104 AN: 1379

European-Non Finnish (NFE) AF: 0.0451 AC: 8968 AN: 198723

Other (OTH) AF: 0.0427 AC: 842 AN: 19696

GnomAD4 genome AF: 0.0414 AC: 4669 AN: 112885 Hom.: 84 Cov.: 24 AF XY: 0.0371 AC XY: 1301 AN XY: 35037

African (AFR) AF: 0.0435 AC: 1356 AN: 31140

American (AMR) AF: 0.0406 AC: 437 AN: 10775

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 179 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00805 AC: 22 AN: 2734

European-Finnish (FIN) AF: 0.0199 AC: 125 AN: 6281

Middle Eastern (MID) AF: 0.0876 AC: 19 AN: 217

European-Non Finnish (NFE) AF: 0.0454 AC: 2419 AN: 53288

Other (OTH) AF: 0.0553 AC: 85 AN: 1538

Alfa AF: 0.0156 Hom.: 97

Bravo AF: 0.0435

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.77
PhyloP100		-0.69
PromoterAI		-0.0062	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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;