X-136209863-C-T

Variant names:

• chrX-136209863-C-T
• rs2076705
• NM_001159702.3:c.889-8C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001159699.2(FHL1):​c.737-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.50 (10115 hom., 14664 hem., cov: 20)
  • Exomes 𝑓: 0.54 (106771 hom. 182938 hem.)
  • Failed GnomAD Quality Control
• Consequence: FHL1 NM_001159699.2 splice_region, intron
• Scores: Splicing: ADA: 0.00007098
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.111
• Publications: 6 publications found

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]

FHL1 Gene-Disease associations (from GenCC):

• X-linked myopathy with postural muscle atrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myopathy, reducing body, X-linked, early-onset, severe

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• reducing body myopathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked scapuloperoneal muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-136209863-C-T is Benign according to our data. Variant chrX-136209863-C-T is described in ClinVar as Benign. ClinVar VariationId is 198466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159699.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	NM_001159702.3	MANE Plus Clinical	c.889-8C>T		splice_region intron	N/A	NP_001153174.1
	FHL1	NM_001159699.2	MANE Select	c.737-8C>T		splice_region intron	N/A	NP_001153171.1
	FHL1	NM_001440769.1		c.937-8C>T		splice_region intron	N/A	NP_001427698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.889-8C>T		splice_region intron	N/A	ENSP00000377710.2
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.737-8C>T		splice_region intron	N/A	ENSP00000359717.1
	FHL1	ENST00000543669.5	TSL:1	c.689-8C>T		splice_region intron	N/A	ENSP00000443333.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 53570 AN: 106685 Hom.: 10113 Cov.: 20

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.449

GnomAD2 exomes AF: 0.517 AC: 87246 AN: 168780 AF XY: 0.492

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.679

Gnomad FIN exome AF: 0.614

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.496

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.541 AC: 578109 AN: 1069496 Hom.: 106771 Cov.: 32 AF XY: 0.536 AC XY: 182938 AN XY: 341272

African (AFR) AF: 0.376 AC: 9569 AN: 25422

American (AMR) AF: 0.539 AC: 18223 AN: 33793

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 9051 AN: 18905

East Asian (EAS) AF: 0.649 AC: 19243 AN: 29670

South Asian (SAS) AF: 0.481 AC: 25142 AN: 52267

European-Finnish (FIN) AF: 0.629 AC: 24984 AN: 39690

Middle Eastern (MID) AF: 0.395 AC: 1397 AN: 3541

European-Non Finnish (NFE) AF: 0.544 AC: 446989 AN: 821336

Other (OTH) AF: 0.524 AC: 23511 AN: 44872

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.502 AC: 53581 AN: 106725 Hom.: 10115 Cov.: 20 AF XY: 0.495 AC XY: 14664 AN XY: 29643

African (AFR) AF: 0.384 AC: 11211 AN: 29209

American (AMR) AF: 0.491 AC: 4889 AN: 9967

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1241 AN: 2597

East Asian (EAS) AF: 0.695 AC: 2342 AN: 3372

South Asian (SAS) AF: 0.479 AC: 1143 AN: 2385

European-Finnish (FIN) AF: 0.627 AC: 3188 AN: 5085

Middle Eastern (MID) AF: 0.354 AC: 74 AN: 209

European-Non Finnish (NFE) AF: 0.550 AC: 28507 AN: 51800

Other (OTH) AF: 0.452 AC: 653 AN: 1445

Alfa AF: 0.532 Hom.: 11616

Bravo AF: 0.492

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	X-linked myopathy with postural muscle atrophy (2)
-	-	1	Myopathy, reducing body, X-linked, childhood-onset (1)
-	-	1	Myopathy, reducing body, X-linked, early-onset, severe (1)
-	-	1	not provided (1)
-	-	1	Uruguay Faciocardiomusculoskeletal syndrome (1)
-	-	1	X-linked scapuloperoneal muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.048
DANN	Benign	0.34
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.072
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

Other links and lift over

dbSNP: rs2076705; hg19: chrX-135292022; COSMIC: COSV61783464; COSMIC: COSV61783464;