rs914754937

Positions:

• chrX-136209862-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001159702.3(FHL1):​c.889-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,170,211 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 72 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 0.00019 (0 hom., 7 hem., cov: 21)
  • Exomes 𝑓: 0.00017 (0 hom. 65 hem.)
• Consequence: FHL1 NM_001159702.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008933
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.586

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 (BayesDel_noAF=-0.94).
• BP6: Variant X-136209862-T-C is Benign according to our data. Variant chrX-136209862-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 391549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000192 (21/109207) while in subpopulation EAS AF= 0.000575 (2/3480). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159699.2	c.737-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370683.6
FHL1	NM_001159702.3	c.889-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000394155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000370683.6	c.737-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001159699.2	P1
FHL1	ENST00000394155.8	c.889-9T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001159702.3

Frequencies

GnomAD3 genomes AF: 0.000192 AC: 21 AN: 109163 Hom.: 0 Cov.: 21 AF XY: 0.000221 AC XY: 7 AN XY: 31681

Gnomad AFR AF: 0.000433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000977

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000573

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000955

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000166 AC: 28 AN: 168269 Hom.: 0 AF XY: 0.000223 AC XY: 13 AN XY: 58243

Gnomad AFR exome AF: 0.000318

Gnomad AMR exome AF: 0.000316

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000406

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 183 AN: 1061004 Hom.: 0 Cov.: 30 AF XY: 0.000189 AC XY: 65 AN XY: 344356

Gnomad4 AFR exome AF: 0.000349

Gnomad4 AMR exome AF: 0.000267

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000172

Gnomad4 SAS exome AF: 0.000250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.0000897

GnomAD4 genome AF: 0.000192 AC: 21 AN: 109207 Hom.: 0 Cov.: 21 AF XY: 0.000221 AC XY: 7 AN XY: 31737

Gnomad4 AFR AF: 0.000432

Gnomad4 AMR AF: 0.0000976

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000575

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000956

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000427 Hom.: 2

Bravo AF: 0.000166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.82
DANN	Benign	0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000089
dbscSNV1_RF	Benign	0.032
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: rs914754937; hg19: chrX-135292021;