rs768705041

Variant names:

• chrX-136209943-A-G
• rs768705041
• NM_001159702.3:c.961A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_001159699.2(FHL1):​c.809A>G​(p.Lys270Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,208,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000022 (0 hom. 11 hem.)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.85
• 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), 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 -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_001159699.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.082158655).
• BP6: Variant X-136209943-A-G is Benign according to our data. Variant chrX-136209943-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469631.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000271 (3/110580) while in subpopulation EAS AF = 0.00085 (3/3529). AF 95% confidence interval is 0.000231. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 3 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.961A>G	p.Asn321Asp	missense	Exon 8 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001159699.2	MANE Select	c.809A>G	p.Lys270Arg	missense	Exon 6 of 6	NP_001153171.1	Q13642-5
	FHL1	NM_001440769.1		c.1009A>G	p.Asn337Asp	missense	Exon 7 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.961A>G	p.Asn321Asp	missense	Exon 8 of 8	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.809A>G	p.Lys270Arg	missense	Exon 6 of 6	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.761A>G	p.Lys254Arg	missense	Exon 6 of 6	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110532 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000847

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

GnomAD2 exomes AF: 0.0000981 AC: 18 AN: 183524 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 24 AN: 1098223 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 11 AN XY: 363577

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

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

East Asian (EAS) AF: 0.000530 AC: 16 AN: 30206

South Asian (SAS) AF: 0.000129 AC: 7 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842113

Other (OTH) AF: 0.0000217 AC: 1 AN: 46095

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110580 Hom.: 0 Cov.: 22 AF XY: 0.0000914 AC XY: 3 AN XY: 32814

African (AFR) AF: 0.00 AC: 0 AN: 30410

American (AMR) AF: 0.00 AC: 0 AN: 10391

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.000850 AC: 3 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2545

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5821

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52849

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000107 AC: 13

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	-	1	X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.73	T
PhyloP100		5.9
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.27
Sift	Benign	0.43	T
Sift4G	Benign	0.36	T
Vest4		0.29
MutPred		0.43		Loss of methylation at K283 (P = 0.0248)
MVP		0.93
ClinPred		0.17	T
GERP RS		5.6
Varity_R		0.41
Mutation Taster		=94/6	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: rs768705041; hg19: chrX-135292102;