X-136206498-G-C

Variant names:

• chrX-136206498-G-C
• rs140149764
• NM_001159702.3:c.66G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001159702.3(FHL1):​c.66G>C​(p.Lys22Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K22Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.66G>C	p.Lys22Asn	missense_variant	Exon 3 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.114G>C	p.Lys38Asn	missense_variant	Exon 2 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.66G>C	p.Lys22Asn	missense_variant	Exon 3 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.114G>C	p.Lys38Asn	missense_variant	Exon 2 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	0.00093	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;.;T;.;T;T;T;.;.;T;T;.;T;T;.;.;T;.;T;T;.;.;.;T;T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.0	.;D;.;D;D;D;D;D;D;.;D;.;.;D;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.55	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	0.56	D
MutationAssessor	Pathogenic	2.9	M;M;M;.;M;.;.;.;.;M;.;.;M;.;.;M;M;.;.;.;M;.;.;.;.;.;M
PhyloP100		2.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.0	.;N;N;.;.;D;N;.;.;.;.;D;N;.;D;N;N;D;.;D;N;.;D;N;N;D;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;T;D;.;.;T;T;.;.;.;.;D;D;.;D;D;D;T;.;T;T;.;D;D;T;D;.
Sift4G	Uncertain	0.014	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
Vest4		0.41
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		0.035	Neutral
Varity_R		0.64
Mutation Taster		=14/86	disease causing

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: rs140149764; hg19: chrX-135288657;