rs754308516

Variant names:

• chrX-136209921-G-A
• rs754308516
• NM_001159699.2:c.787G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-136209921-G-A
• chrX-136209921-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4 BS1_Supporting BS2

The NM_001159699.2(FHL1):​c.787G>A​(p.Asp263Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,208,369 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D263D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000015 (0 hom. 3 hem.)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.76
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001159699.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.30665517).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000998 (11/110218) while in subpopulation AMR AF = 0.00029 (3/10336). AF 95% confidence interval is 0.0000858. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159699.2	c.787G>A	p.Asp263Asn	missense_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1
FHL1	NM_001159702.3	c.939G>A	p.Thr313Thr	synonymous_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000370683.6	c.787G>A	p.Asp263Asn	missense_variant	Exon 6 of 6	1	NM_001159699.2	ENSP00000359717.1
FHL1	ENST00000394155.8	c.939G>A	p.Thr313Thr	synonymous_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes AF: 0.0000908 AC: 10 AN: 110168 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000194

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: 0.0000189

Gnomad OTH AF: 0.000679

GnomAD2 exomes AF: 0.0000709 AC: 13 AN: 183475 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1098151 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 3 AN XY: 363509

African (AFR) AF: 0.0000379 AC: 1 AN: 26402

American (AMR) AF: 0.000256 AC: 9 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30204

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4105

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842084

Other (OTH) AF: 0.0000217 AC: 1 AN: 46090

GnomAD4 genome AF: 0.0000998 AC: 11 AN: 110218 Hom.: 0 Cov.: 22 AF XY: 0.0000615 AC XY: 2 AN XY: 32498

African (AFR) AF: 0.000198 AC: 6 AN: 30321

American (AMR) AF: 0.000290 AC: 3 AN: 10336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3503

South Asian (SAS) AF: 0.00 AC: 0 AN: 2521

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52792

Other (OTH) AF: 0.000671 AC: 1 AN: 1491

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Uruguay Faciocardiomusculoskeletal syndrome;C2678055:X-linked myopathy with postural muscle atrophy;C2678061:X-linked scapuloperoneal muscular dystrophy;C4225159:Myopathy, reducing body, X-linked, childhood-onset;C4225423:Myopathy, reducing body, X-linked, early-onset, severe Uncertain:1

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked myopathy with postural muscle atrophy Uncertain:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 247 of the FHL1 protein (p.Asp247Asn). This variant is present in population databases (rs754308516, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 198467). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Nov 26, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Mar 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D247N variant (also known as c.739G>A), located in coding exon 5 of the FHL1 gene, results from a G to A substitution at nucleotide position 739. The aspartic acid at codon 247 is replaced by asparagine, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.007% (14/204575) total alleles studied, with 3 hemizygote(s) observed. The highest observed frequency was 0.032% (9/28039) of Latino alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;.;.;.;.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	.;.;.;.;.;T;T;T;D;.
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
PhyloP100		7.8
PROVEAN	Benign	0.25	.;N;.;N;N;N;N;N;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.98	.;T;.;T;T;T;T;T;T;.
Sift4G	Benign	0.88	T;T;T;T;T;T;T;T;T;T
Vest4		0.29
MVP		0.98
ClinPred		0.078	T
GERP RS		5.6
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754308516; hg19: chrX-135292080; COSMIC: COSV104422446; COSMIC: COSV104422446;