NM_001159702.3:c.-26-9547G>A

Variant names:

• chrX-136196860-G-A
• rs192893870
• NM_001159702.3:c.-26-9547G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001159702.3(FHL1):​c.-26-9547G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,163,238 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 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 0.00035 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 48 hem.)
• Consequence: FHL1 NM_001159702.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.10
• Publications: 3 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 (MetaRNN=0.008448601).
• BP6: Variant X-136196860-G-A is Benign according to our data. Variant chrX-136196860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 993975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00035 (39/111409) while in subpopulation AMR AF = 0.00171 (18/10496). AF 95% confidence interval is 0.00111. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-26-9547G>A		intron_variant	Intron 2 of 7	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.-253G>A		upstream_gene_variant		ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-26-9547G>A		intron_variant	Intron 2 of 7	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.-253G>A		upstream_gene_variant		1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes AF: 0.000350 AC: 39 AN: 111355 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000686

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

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

GnomAD2 exomes AF: 0.000990 AC: 112 AN: 113170 AF XY: 0.000693

Gnomad AFR exome AF: 0.000469

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 170 AN: 1051829 Hom.: 0 Cov.: 29 AF XY: 0.000140 AC XY: 48 AN XY: 342801

African (AFR) AF: 0.000603 AC: 15 AN: 24867

American (AMR) AF: 0.00463 AC: 129 AN: 27887

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18622

East Asian (EAS) AF: 0.00 AC: 0 AN: 27127

South Asian (SAS) AF: 0.0000201 AC: 1 AN: 49749

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3880

European-Non Finnish (NFE) AF: 0.0000269 AC: 22 AN: 817819

Other (OTH) AF: 0.0000677 AC: 3 AN: 44290

GnomAD4 genome AF: 0.000350 AC: 39 AN: 111409 Hom.: 0 Cov.: 23 AF XY: 0.000535 AC XY: 18 AN XY: 33633

African (AFR) AF: 0.000684 AC: 21 AN: 30686

American (AMR) AF: 0.00171 AC: 18 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.00 AC: 0 AN: 2581

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53079

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000774

ExAC AF: 0.0000655 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 27, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FHL1-related disorder Benign:1

Jan 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.8
DANN	Benign	0.77
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.1
PROVEAN	Benign	0.070	N
REVEL	Benign	0.080
Sift	Benign	0.54	T
Sift4G	Benign	0.63	T
Vest4		0.12
MVP		0.43
ClinPred		0.0024	T
GERP RS		-4.1
PromoterAI		0.032	Neutral
Mutation Taster		=96/4	polymorphism

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: rs192893870; hg19: chrX-135279019; COSMIC: COSV61782755; COSMIC: COSV61782755;