X-136147722-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001159702.3(FHL1):​c.-101+94C>G variant causes a intron 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 0.014 (16 hom., 394 hem., cov: 19)
  • Exomes 𝑓: 0.0016 (0 hom. 0 hem.)
• Consequence: FHL1 NM_001159702.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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), 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-136147722-C-G is Benign according to our data. Variant chrX-136147722-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1212687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (1528/107918) while in subpopulation AFR AF = 0.0207 (618/29785). AF 95% confidence interval is 0.0194. There are 16 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-101+94C>G		intron_variant	Intron 1 of 7	ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-101+94C>G		intron_variant	Intron 1 of 7	5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 1527 AN: 107884 Hom.: 16 Cov.: 19

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.0474

Gnomad EAS AF: 0.00752

Gnomad SAS AF: 0.00203

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.0174

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00164 AC: 1 AN: 608 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 186

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

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: 0.00247 AC: 1 AN: 405

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0142 AC: 1528 AN: 107918 Hom.: 16 Cov.: 19 AF XY: 0.0128 AC XY: 394 AN XY: 30860

African (AFR) AF: 0.0207 AC: 618 AN: 29785

American (AMR) AF: 0.00857 AC: 89 AN: 10391

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 124 AN: 2617

East Asian (EAS) AF: 0.00756 AC: 25 AN: 3309

South Asian (SAS) AF: 0.00245 AC: 6 AN: 2449

European-Finnish (FIN) AF: 0.00509 AC: 28 AN: 5497

Middle Eastern (MID) AF: 0.0191 AC: 4 AN: 209

European-Non Finnish (NFE) AF: 0.0103 AC: 533 AN: 51570

Other (OTH) AF: 0.0137 AC: 20 AN: 1458

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0149

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 21, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.2
DANN	Benign	0.50
PhyloP100		-2.1
PromoterAI		0.0085	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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;