X-136206402-C-T

Position:

• chrX-136206402-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001159702.3(FHL1):​c.-26-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000752 in 1,210,320 control chromosomes in the GnomAD database, including 7 homozygotes. There are 511 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 9 hem., cov: 24)
  • Exomes 𝑓: 0.00080 (7 hom. 502 hem.)
• Consequence: FHL1 NM_001159702.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005128
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.399

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-136206402-C-T is Benign according to our data. Variant chrX-136206402-C-T is described in ClinVar as [Benign]. Clinvar id is 386800.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-136206402-C-T is described in Lovd as [Benign]. Variant chrX-136206402-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000258 (29/112266) while in subpopulation SAS AF= 0.00972 (26/2674). AF 95% confidence interval is 0.00681. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159699.2	c.23-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370683.6
FHL1	NM_001159702.3	c.-26-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000370683.6	c.23-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001159699.2	P1
FHL1	ENST00000394155.8	c.-26-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001159702.3

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 29 AN: 112210 Hom.: 0 Cov.: 24 AF XY: 0.000262 AC XY: 9 AN XY: 34366

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00969

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00166 AC: 305 AN: 183389 Hom.: 3 AF XY: 0.00274 AC XY: 186 AN XY: 67843

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000802 AC: 881 AN: 1098054 Hom.: 7 Cov.: 31 AF XY: 0.00138 AC XY: 502 AN XY: 363422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000214

Gnomad4 OTH exome AF: 0.000933

GnomAD4 genome AF: 0.000258 AC: 29 AN: 112266 Hom.: 0 Cov.: 24 AF XY: 0.000261 AC XY: 9 AN XY: 34432

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00972

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 2

Bravo AF: 0.000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.2
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0060
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: rs374346567; hg19: chrX-135288561;