rs9018

Variant names:

• chrX-136210923-G-A
• rs9018
• NM_001159702.3:c.*969G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001159699.2(FHL1):​c.*898G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 380,390 control chromosomes in the GnomAD database, including 30,721 homozygotes. There are 65,789 hemizygotes 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 0.47 (8823 hom., 16104 hem., cov: 23)
  • Exomes 𝑓: 0.50 (21898 hom. 49685 hem.)
• Consequence: FHL1 NM_001159699.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.802
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.*969G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.*898G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.*969G>A		3_prime_UTR_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.*898G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 52758 AN: 111239 Hom.: 8821 Cov.: 23

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.696

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.343

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.513 AC: 48925 AN: 95413 AF XY: 0.507

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.543

Gnomad ASJ exome AF: 0.435

Gnomad EAS exome AF: 0.710

Gnomad FIN exome AF: 0.624

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.476

GnomAD4 exome AF: 0.503 AC: 135336 AN: 269093 Hom.: 21898 Cov.: 0 AF XY: 0.501 AC XY: 49685 AN XY: 99129

African (AFR) AF: 0.390 AC: 3676 AN: 9425

American (AMR) AF: 0.535 AC: 12412 AN: 23198

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 4830 AN: 11085

East Asian (EAS) AF: 0.655 AC: 9444 AN: 14422

South Asian (SAS) AF: 0.482 AC: 17383 AN: 36040

European-Finnish (FIN) AF: 0.612 AC: 5770 AN: 9433

Middle Eastern (MID) AF: 0.377 AC: 418 AN: 1108

European-Non Finnish (NFE) AF: 0.497 AC: 74141 AN: 149319

Other (OTH) AF: 0.482 AC: 7262 AN: 15063

GnomAD4 genome AF: 0.474 AC: 52785 AN: 111297 Hom.: 8823 Cov.: 23 AF XY: 0.480 AC XY: 16104 AN XY: 33525

African (AFR) AF: 0.387 AC: 11852 AN: 30644

American (AMR) AF: 0.476 AC: 5028 AN: 10564

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1163 AN: 2624

East Asian (EAS) AF: 0.696 AC: 2450 AN: 3518

South Asian (SAS) AF: 0.474 AC: 1248 AN: 2634

European-Finnish (FIN) AF: 0.611 AC: 3636 AN: 5954

Middle Eastern (MID) AF: 0.312 AC: 67 AN: 215

European-Non Finnish (NFE) AF: 0.498 AC: 26359 AN: 52950

Other (OTH) AF: 0.434 AC: 663 AN: 1528

Alfa AF: 0.492 Hom.: 9502

Bravo AF: 0.463

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.8
DANN	Benign	0.69
PhyloP100		0.80
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: rs9018; hg19: chrX-135293082;