rs149670651

chrX-136207901-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001159702.3(FHL1):c.441C>T(p.Asp147=) 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_001159702.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.351

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 239009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136207901-C-T is described in Lovd as [Benign]. Variant chrX-136207901-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.441C>T	p.Asp147=	synonymous_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.489C>T	p.Asp163=	synonymous_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.441C>T	p.Asp147=	synonymous_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.489C>T	p.Asp163=	synonymous_variant	4/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 176 AN: 112846 Hom.: 0 Cov.: 23 AF XY: 0.00163 AC XY: 57 AN XY: 34986

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

GnomAD3 exomes AF: 0.00165 AC: 303 AN: 183432 Hom.: 1 AF XY: 0.00183 AC XY: 124 AN XY: 67870

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 SAS exome AF: 0.000943

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

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.000653

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00336

Gnomad4 NFE exome AF: 0.00311

Gnomad4 OTH exome AF: 0.00184

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

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000735

Gnomad4 FIN AF: 0.00177

Gnomad4 NFE AF: 0.00277

Gnomad4 OTH AF: 0.000647

Alfa AF: 0.00200 Hom.: 16

Bravo AF: 0.00131

EpiCase AF: 0.00207

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	This variant is associated with the following publications: (PMID: 22523091, 19377476) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

X-linked myopathy with postural muscle atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Familial hemophagocytic lymphohistiocytosis type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 26, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	12
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs149670651; hg19: chrX-135290060;