rs146125558

Variant names:

• chrX-136206437-C-T
• rs146125558
• NM_001159702.3:c.5C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001159699.2(FHL1):​c.53C>T​(p.Ala18Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,210,710 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A18A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000022 (0 hom. 8 hem.)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.90
• Publications: 5 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), G2P, Orphanet
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33708543).
• BP6: Variant X-136206437-C-T is Benign according to our data. Variant chrX-136206437-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289087.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000445 (5/112482) while in subpopulation NFE AF = 0.0000939 (5/53225). AF 95% confidence interval is 0.0000369. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159699.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	NM_001159702.3	MANE Plus Clinical	c.5C>T	p.Ala2Val	missense	Exon 3 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001159699.2	MANE Select	c.53C>T	p.Ala18Val	missense	Exon 2 of 6	NP_001153171.1	Q13642-5
	FHL1	NM_001440769.1		c.53C>T	p.Ala18Val	missense	Exon 2 of 7	NP_001427698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.5C>T	p.Ala2Val	missense	Exon 3 of 8	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.53C>T	p.Ala18Val	missense	Exon 2 of 6	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.5C>T	p.Ala2Val	missense	Exon 2 of 6	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes AF: 0.0000445 AC: 5 AN: 112482 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000939

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000327 AC: 6 AN: 183451 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 24 AN: 1098228 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8 AN XY: 363582

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.0000493 AC: 2 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.0000237 AC: 20 AN: 842134

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome AF: 0.0000445 AC: 5 AN: 112482 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34640

African (AFR) AF: 0.00 AC: 0 AN: 30942

American (AMR) AF: 0.00 AC: 0 AN: 10723

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6209

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000939 AC: 5 AN: 53225

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not specified (1)
-	1	-	X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Benign	0.072	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.82	P
Vest4		0.14
MVP		0.73
MPC		0.50
ClinPred		0.30	T
GERP RS		5.7
PromoterAI		-0.046	Neutral
Varity_R		0.18
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: rs146125558; hg19: chrX-135288596; COSMIC: COSV61779475; COSMIC: COSV61779475;