rs1343871742

Positions:

• chrX-136207034-C-A
• chrX-136207034-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001159702.3(FHL1):​c.175C>A​(p.Arg59Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.175C>A	p.Arg59Ser	missense_variant	4/8	ENST00000394155.8
FHL1	NM_001159699.2	c.223C>A	p.Arg75Ser	missense_variant	3/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.175C>A	p.Arg59Ser	missense_variant	4/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.223C>A	p.Arg75Ser	missense_variant	3/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111866 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34048

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000285

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111866 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34048

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000285

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.3	M;M;M;.;M;.;.;.;.;M;.;.;M;.;.;M;M;.;.;.;M;.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.0080	D;D;D;T;T;D;T;T;T;D;T;D;D;D;D;D;D;D;D;T;D;T;D;D;T;D;D
Polyphen		0.99	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.85
MutPred		0.72		Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);.;.;.;Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);
MVP		1.0
MPC		1.4
ClinPred		0.85	D
GERP RS		5.1
Varity_R		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs1343871742; hg19: chrX-135289193;