NM_001159702.3:c.-20C>G

Variant names:

• chrX-136206413-C-G
• rs1603270381
• NM_001159702.3:c.-20C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001159702.3(FHL1):​c.-20C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000911 in 1,098,179 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: FHL1 NM_001159702.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.62
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3204331).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-20C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.29C>G	p.Ser10Cys	missense_variant	Exon 2 of 6	ENST00000370683.6	NP_001153171.1
FHL1	NM_001159702.3	c.-20C>G		5_prime_UTR_variant	Exon 3 of 8	ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-20C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.29C>G	p.Ser10Cys	missense_variant	Exon 2 of 6	1	NM_001159699.2	ENSP00000359717.1
FHL1	ENST00000394155.8	c.-20C>G		5_prime_UTR_variant	Exon 3 of 8	5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098179 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363539

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35206

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842118

Other (OTH) AF: 0.0000217 AC: 1 AN: 46087

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked scapuloperoneal muscular dystrophy Uncertain:1

-

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	.;.;T
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.82	T;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.83	T
PhyloP100		3.6
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.027	D;D;D
Vest4		0.45
MutPred		0.39		Loss of disorder (P = 4e-04);.;.;
MVP		0.60
ClinPred		0.66	D
GERP RS		4.8
PromoterAI		-0.0081	Neutral
Mutation Taster		=93/7	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: rs1603270381; hg19: chrX-135288572;