rs754404850

Variant names:

• chrX-136209859-TTTTC-T
• rs754404850
• NM_001159702.3:c.889-11_889-8delTTTC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001159699.2(FHL1):​c.737-11_737-8delTTTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,202,652 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 3 hem., cov: 20)
  • Exomes 𝑓: 0.00012 (0 hom. 43 hem.)
• Consequence: FHL1 NM_001159699.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.61

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 -10 ACMG points.

• BP6: Variant X-136209859-TTTTC-T is Benign according to our data. Variant chrX-136209859-TTTTC-T is described in ClinVar as [Likely_benign]. Clinvar id is 537361.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-136209859-TTTTC-T is described in Lovd as [Likely_benign]. Variant chrX-136209859-TTTTC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000109 (12/110211) while in subpopulation EAS AF= 0.000285 (1/3506). AF 95% confidence interval is 0.000089. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.889-11_889-8delTTTC		splice_region_variant, intron_variant	Intron 7 of 7	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.737-11_737-8delTTTC		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.889-11_889-8delTTTC		splice_region_variant, intron_variant	Intron 7 of 7	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.737-11_737-8delTTTC		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes AF: 0.000109 AC: 12 AN: 110159 Hom.: 0 Cov.: 20 AF XY: 0.0000925 AC XY: 3 AN XY: 32445

Gnomad AFR AF: 0.0000662

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000171

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 130 AN: 1092441 Hom.: 0 AF XY: 0.000119 AC XY: 43 AN XY: 360647

Gnomad4 AFR exome AF: 0.000228

Gnomad4 AMR exome AF: 0.0000286

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.0000994

Gnomad4 SAS exome AF: 0.000482

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome AF: 0.000109 AC: 12 AN: 110211 Hom.: 0 Cov.: 20 AF XY: 0.0000923 AC XY: 3 AN XY: 32507

Gnomad4 AFR AF: 0.0000661

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000285

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000171

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

X-linked myopathy with postural muscle atrophy Benign:1

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs754404850; hg19: chrX-135292018;