rs149670651

Variant names:

• chrX-136207901-C-T
• rs149670651
• NM_001159702.3:c.441C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-136207901-C-T
• chrX-136207901-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001159699.2(FHL1):​c.489C>T​(p.Asp163Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,211,068 control chromosomes in the GnomAD database, including 8 homozygotes. There are 995 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 57 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (8 hom. 938 hem.)
• Consequence: FHL1 NM_001159699.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.351
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-136207901-C-T is Benign according to our data. Variant chrX-136207901-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.351 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00156 (176/112899) while in subpopulation NFE AF = 0.00277 (148/53343). AF 95% confidence interval is 0.00241. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 57 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.441C>T	p.Asp147Asp	synonymous	Exon 5 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001159699.2	MANE Select	c.489C>T	p.Asp163Asp	synonymous	Exon 4 of 6	NP_001153171.1	Q13642-5
	FHL1	NM_001440769.1		c.489C>T	p.Asp163Asp	synonymous	Exon 4 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.441C>T	p.Asp147Asp	synonymous	Exon 5 of 8	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.489C>T	p.Asp163Asp	synonymous	Exon 4 of 6	ENSP00000359717.1	Q13642-5
	FHL1	ENST00000543669.5	TSL:1	c.441C>T	p.Asp147Asp	synonymous	Exon 4 of 6	ENSP00000443333.1	Q13642-1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 176 AN: 112846 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000733

Gnomad FIN AF: 0.00177

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00277

Gnomad OTH AF: 0.000655

GnomAD2 exomes AF: 0.00165 AC: 303 AN: 183432 AF XY: 0.00183

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00267 AC: 2936 AN: 1098169 Hom.: 8 Cov.: 31 AF XY: 0.00258 AC XY: 938 AN XY: 363527

African (AFR) AF: 0.000303 AC: 8 AN: 26400

American (AMR) AF: 0.000653 AC: 23 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: 0.00118 AC: 64 AN: 54147

European-Finnish (FIN) AF: 0.00336 AC: 136 AN: 40533

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.00311 AC: 2618 AN: 842060

Other (OTH) AF: 0.00184 AC: 85 AN: 46094

GnomAD4 genome AF: 0.00156 AC: 176 AN: 112899 Hom.: 0 Cov.: 23 AF XY: 0.00163 AC XY: 57 AN XY: 35049

African (AFR) AF: 0.000289 AC: 9 AN: 31166

American (AMR) AF: 0.000464 AC: 5 AN: 10772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.000735 AC: 2 AN: 2722

European-Finnish (FIN) AF: 0.00177 AC: 11 AN: 6223

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00277 AC: 148 AN: 53343

Other (OTH) AF: 0.000647 AC: 1 AN: 1545

Alfa AF: 0.00200 Hom.: 16

Bravo AF: 0.00131

EpiCase AF: 0.00207

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial hemophagocytic lymphohistiocytosis type 1 (1)
-	-	1	X-linked myopathy with postural muscle atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.50
PhyloP100		0.35
Mutation Taster		=98/2	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: rs149670651; hg19: chrX-135290060;