X-136147722-C-T

Variant names:

• chrX-136147722-C-T
• rs374235006
• NM_001159702.3:c.-101+94C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001369326.1(FHL1):​c.-257C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., 1 hem., cov: 19)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FHL1 NM_001369326.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369326.1. 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.-101+94C>T		intron	N/A	NP_001153174.1	Q13642-2
	FHL1	NM_001369326.1		c.-257C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001356255.1	Q13642-2
	FHL1	NM_001369329.1		c.-257C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001356258.1	Q13642-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.-101+94C>T		intron	N/A	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000651089.1		c.-399C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000498684.1	Q13642-2
	FHL1	ENST00000420362.5	TSL:2	c.-257C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000391779.1	Q5JXH8

Frequencies

GnomAD3 genomes AF: 0.0000649 AC: 7 AN: 107889 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 608 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 186

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1

East Asian (EAS) AF: 0.00 AC: 0 AN: 13

South Asian (SAS) AF: 0.00 AC: 0 AN: 156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 405

Other (OTH) AF: 0.00 AC: 0 AN: 21

GnomAD4 genome AF: 0.0000649 AC: 7 AN: 107889 Hom.: 0 Cov.: 19 AF XY: 0.0000324 AC XY: 1 AN XY: 30817

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

African (AFR) AF: 0.000235 AC: 7 AN: 29731

American (AMR) AF: 0.00 AC: 0 AN: 10379

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2618

East Asian (EAS) AF: 0.00 AC: 0 AN: 3323

South Asian (SAS) AF: 0.00 AC: 0 AN: 2458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5497

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51581

Other (OTH) AF: 0.00 AC: 0 AN: 1439

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000397875), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.6
DANN	Benign	0.85
PhyloP100		-2.1
PromoterAI		-0.068	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs374235006; hg19: chrX-135229881;