rs367592190

chrX-136209314-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001159702.3(FHL1):c.760C>T(p.Arg254Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,208,993 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.000027 (0 hom. 8 hem.)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.03

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14491272).
• BP6: Variant X-136209314-C-T is Benign according to our data. Variant chrX-136209314-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290191.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000216 (24/111059) while in subpopulation AFR AF= 0.000657 (20/30448). AF 95% confidence interval is 0.000435. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.760C>T	p.Arg254Cys	missense_variant	7/8	ENST00000394155.8
FHL1	NM_001159699.2	c.737-557C>T		intron_variant		ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.760C>T	p.Arg254Cys	missense_variant	7/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.737-557C>T		intron_variant		1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes AF: 0.000216 AC: 24 AN: 111059 Hom.: 0 Cov.: 22 AF XY: 0.000211 AC XY: 7 AN XY: 33235

Gnomad AFR AF: 0.000657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000663 AC: 12 AN: 180955 Hom.: 0 AF XY: 0.0000594 AC XY: 4 AN XY: 67323

Gnomad AFR exome AF: 0.000568

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000273 AC: 30 AN: 1097934 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8 AN XY: 363374

Gnomad4 AFR exome AF: 0.000682

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.000216 AC: 24 AN: 111059 Hom.: 0 Cov.: 22 AF XY: 0.000211 AC XY: 7 AN XY: 33235

Gnomad4 AFR AF: 0.000657

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000755

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.000761 AC: 2

ESP6500EA AF: 0.000182 AC: 1

ExAC AF: 0.0000996 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 01, 2018

- -

X-linked myopathy with postural muscle atrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	20
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.87	D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.96	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	2.1	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.32
MVP		0.93
MPC		1.3
ClinPred		0.13	T
GERP RS		3.9
Varity_R		0.20

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: rs367592190; hg19: chrX-135291473; COSMIC: COSV105241237; COSMIC: COSV105241237;