rs151315725

chrX-136210005-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. 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:12
• Conservation: PhyloP100: 6.32

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 -20 ACMG points.

• 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 id is 239013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136210005-G-A is described in Lovd as [Benign]. Variant chrX-136210005-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159699.2	c.871G>A	p.Asp291Asn	missense_variant	6/6	ENST00000370683.6
FHL1	NM_001159702.3	c.*51G>A		3_prime_UTR_variant	8/8	ENST00000394155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000370683.6	c.871G>A	p.Asp291Asn	missense_variant	6/6	1	NM_001159699.2	P1
FHL1	ENST00000394155.8	c.*51G>A		3_prime_UTR_variant	8/8	5	NM_001159702.3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1274 AN: 110492 Hom.: 9 Cov.: 22 AF XY: 0.0101 AC XY: 329 AN XY: 32716

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

GnomAD3 exomes AF: 0.0109 AC: 1994 AN: 183528 Hom.: 17 AF XY: 0.0113 AC XY: 765 AN XY: 67958

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 SAS exome AF: 0.00535

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

Gnomad4 AFR exome AF: 0.00208

Gnomad4 AMR exome AF: 0.00648

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00624

Gnomad4 FIN exome AF: 0.00570

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0125

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

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.00190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00702

Gnomad4 FIN AF: 0.00362

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.00535

Alfa AF: 0.0164 Hom.: 719

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

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2021	Variant summary: FHL1 c.*51G>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.011 in 183528 control chromosomes in the gnomAD database, including 17 homozygotes. The observed variant frequency is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in FHL1 causing Emery-Dreifuss Muscular Dystrophy phenotype (0.00039), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.*51G>A in individuals affected with Emery-Dreifuss Muscular Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

X-linked myopathy with postural muscle atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Familial hemophagocytic lymphohistiocytosis type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 19, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2019

This alteration is classified as 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_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0082	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.056	T;T;T;T;T;T;T;T;T
Vest4		0.15
ClinPred		0.027	T
GERP RS		5.6

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: rs151315725; hg19: chrX-135292164;