rs878854460

chrX-136207848-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_001159702.3(FHL1):c.388A>G(p.Ser130Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,098,111 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.48

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001159702.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.388A>G	p.Ser130Gly	missense_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.436A>G	p.Ser146Gly	missense_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.388A>G	p.Ser130Gly	missense_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.436A>G	p.Ser146Gly	missense_variant	4/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1098111 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363465

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 130 of the FHL1 protein (p.Ser130Gly). This variant is not present in population databases (gnomAD no frequency). 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: 239008). 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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	21
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.7	L;L;L;.;L;.;.;.;.;L;.;L;.;L;L;.;.;.;L;.;.;.;.;.;L
MutationTaster	Benign	0.76	D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T;T
Polyphen		0.87, 0.19	.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;B;.;.
Vest4		0.47
MutPred		0.39		Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);.;.;.;Loss of catalytic residue at S130 (P = 0.0267);Loss of catalytic residue at S130 (P = 0.0267);
MVP		0.92
MPC		1.3
ClinPred		0.81	D
GERP RS		4.7
Varity_R		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854460; hg19: chrX-135290007;