ENST00000651929.2:c.-261A>C

Variant names:

• chrX-136147468-A-C
• rs28494155
• ENST00000651929.2:c.-261A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000651929.2(FHL1):​c.-261A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (17919 hom., 14859 hem., cov: 15)
  • Exomes 𝑓: 0.69 (87 hom. 93 hem.)
  • Failed GnomAD Quality Control
• Consequence: FHL1 ENST00000651929.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.643
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-136147468-A-C is Benign according to our data. Variant chrX-136147468-A-C is described in ClinVar as [Benign]. Clinvar id is 1248339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-261A>C		upstream_gene_variant		ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-261A>C		upstream_gene_variant		5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes AF: 0.751 AC: 65343 AN: 86956 Hom.: 17917 Cov.: 15

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.695

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.711

GnomAD4 exome AF: 0.694 AC: 359 AN: 517 Hom.: 87 Cov.: 0 AF XY: 0.769 AC XY: 93 AN XY: 121

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.695 AC: 348 AN: 501

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.800 AC: 8 AN: 10

Other (OTH) AF: 0.500 AC: 3 AN: 6

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.751 AC: 65347 AN: 86964 Hom.: 17919 Cov.: 15 AF XY: 0.809 AC XY: 14859 AN XY: 18362

African (AFR) AF: 0.617 AC: 13741 AN: 22270

American (AMR) AF: 0.750 AC: 6153 AN: 8203

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 1654 AN: 2262

East Asian (EAS) AF: 0.683 AC: 1752 AN: 2567

South Asian (SAS) AF: 0.731 AC: 1300 AN: 1778

European-Finnish (FIN) AF: 0.872 AC: 2396 AN: 2747

Middle Eastern (MID) AF: 0.690 AC: 120 AN: 174

European-Non Finnish (NFE) AF: 0.817 AC: 36989 AN: 45259

Other (OTH) AF: 0.712 AC: 841 AN: 1182

Alfa AF: 0.540 Hom.: 1680

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.7
DANN	Benign	0.73
PhyloP100		-0.64
PromoterAI		0.017	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs28494155; hg19: chrX-135229627;