chrX-136210005-G-A

Variant names:

• chrX-136210005-G-A
• rs151315725
• NM_001159699.2:c.871G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001159699.2(FHL1):​c.871G>A​(p.Asp291Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0163 in 1,208,769 control chromosomes in the GnomAD database, including 140 homozygotes. There are 6,223 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (9 hom., 328 hem., cov: 22)
  • Exomes 𝑓: 0.017 (131 hom. 5895 hem.)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 6.32
• Publications: 9 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 -18 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, 13 uncertain in NM_001159699.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0082143545).
• BP6: Variant X-136210005-G-A is Benign according to our data. Variant chrX-136210005-G-A is described in ClinVar as Benign. ClinVar VariationId is 239013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1272/110547) while in subpopulation NFE AF = 0.0194 (1026/52838). AF 95% confidence interval is 0.0184. There are 9 homozygotes in GnomAd4. There are 328 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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_001159699.2	MANE Select	c.871G>A	p.Asp291Asn	missense	Exon 6 of 6	NP_001153171.1	Q13642-5
	FHL1	NM_001159702.3	MANE Plus Clinical	c.*51G>A		3_prime_UTR	Exon 8 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001159701.2		c.910G>A	p.Asp304Asn	missense	Exon 6 of 6	NP_001153173.1	Q13642-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.871G>A	p.Asp291Asn	missense	Exon 6 of 6	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.823G>A	p.Asp275Asn	missense	Exon 6 of 6	ENSP00000443333.1	Q13642-1
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.*51G>A		3_prime_UTR	Exon 8 of 8	ENSP00000377710.2	Q13642-2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1274 AN: 110492 Hom.: 9 Cov.: 22

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00699

Gnomad FIN AF: 0.00362

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.00542

GnomAD2 exomes AF: 0.0109 AC: 1994 AN: 183528 AF XY: 0.0113

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.00627

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.000216

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0167 AC: 18390 AN: 1098222 Hom.: 131 Cov.: 33 AF XY: 0.0162 AC XY: 5895 AN XY: 363582

African (AFR) AF: 0.00208 AC: 55 AN: 26403

American (AMR) AF: 0.00648 AC: 228 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 26 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30202

South Asian (SAS) AF: 0.00624 AC: 338 AN: 54145

European-Finnish (FIN) AF: 0.00570 AC: 231 AN: 40529

Middle Eastern (MID) AF: 0.00435 AC: 18 AN: 4136

European-Non Finnish (NFE) AF: 0.0201 AC: 16916 AN: 842116

Other (OTH) AF: 0.0125 AC: 577 AN: 46098

GnomAD4 genome AF: 0.0115 AC: 1272 AN: 110547 Hom.: 9 Cov.: 22 AF XY: 0.0100 AC XY: 328 AN XY: 32781

African (AFR) AF: 0.00296 AC: 90 AN: 30377

American (AMR) AF: 0.0100 AC: 104 AN: 10397

Ashkenazi Jewish (ASJ) AF: 0.00190 AC: 5 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.00702 AC: 18 AN: 2565

European-Finnish (FIN) AF: 0.00362 AC: 21 AN: 5805

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0194 AC: 1026 AN: 52838

Other (OTH) AF: 0.00535 AC: 8 AN: 1496

Alfa AF: 0.0154 Hom.: 723

Bravo AF: 0.0110

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0232 AC: 67

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.0186 AC: 125

ExAC AF: 0.0112 AC: 1364

EpiCase AF: 0.0160

EpiControl AF: 0.0186

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	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	0.22
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	-0.10	T
PhyloP100		6.3
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.056	T
Vest4		0.15
ClinPred		0.027	T
GERP RS		5.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs151315725; hg19: chrX-135292164; COSMIC: COSV106107115; COSMIC: COSV106107115;