X-136147620-C-A

Variant names:

• chrX-136147620-C-A
• rs1556630646
• NM_001159702.3:c.-109C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001159702.3(FHL1):​c.-109C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.000046 (0 hom., 2 hem., cov: 19)
• Consequence: FHL1 NM_001159702.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.740
• Publications: 0 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), G2P, Orphanet
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant X-136147620-C-A is Benign according to our data. Variant chrX-136147620-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 512539.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159702.3. 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.-109C>A		5_prime_UTR	Exon 1 of 8	NP_001153174.1	Q13642-2
	FHL1	NM_001449.5		c.-109C>A		5_prime_UTR	Exon 1 of 7	NP_001440.2
	FHL1	NM_001159703.2		c.-109C>A		5_prime_UTR	Exon 1 of 6	NP_001153175.1	Q13642-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.-109C>A		5_prime_UTR	Exon 1 of 8	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000651929.2		c.-109C>A		5_prime_UTR	Exon 1 of 7	ENSP00000499016.1	Q13642-1
	FHL1	ENST00000652457.1		c.-109C>A		5_prime_UTR	Exon 1 of 8	ENSP00000498503.1	A0A494C0D6

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 5 AN: 107647 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000386

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: 0.00

Gnomad OTH AF: 0.000695

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000464 AC: 5 AN: 107647 Hom.: 0 Cov.: 19 AF XY: 0.0000655 AC XY: 2 AN XY: 30527

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29764

American (AMR) AF: 0.000386 AC: 4 AN: 10373

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2621

East Asian (EAS) AF: 0.00 AC: 0 AN: 3297

South Asian (SAS) AF: 0.00 AC: 0 AN: 2412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5375

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 227

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51502

Other (OTH) AF: 0.000695 AC: 1 AN: 1439

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000509044), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.97
PhyloP100		0.74
PromoterAI		0.24	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1556630646; hg19: chrX-135229779;