X-136147638-C-G

Variant names:

• chrX-136147638-C-G
• rs1013945435
• NM_001159702.3:c.-101+10C>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+10C>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 0.00035 (0 hom., 7 hem., cov: 19)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FHL1 NM_001159702.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.311
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-136147638-C-G is Benign according to our data. Variant chrX-136147638-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 390490.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000354 (38/107260) while in subpopulation AMR AF = 0.00145 (15/10342). AF 95% confidence interval is 0.000894. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 7 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.-101+10C>G		intron	N/A	NP_001153174.1	Q13642-2
	FHL1	NM_001449.5		c.-101+10C>G		intron	N/A	NP_001440.2
	FHL1	NM_001159703.2		c.-101+10C>G		intron	N/A	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.-101+10C>G		intron	N/A	ENSP00000377710.2	Q13642-2
	FHL1	ENST00000629039.2	TSL:2	c.-101+626C>G		intron	N/A	ENSP00000486439.1	Q13642-1
	FHL1	ENST00000651929.2		c.-101+10C>G		intron	N/A	ENSP00000499016.1	Q13642-1

Frequencies

GnomAD3 genomes AF: 0.000354 AC: 38 AN: 107222 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

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: 0.000408

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 620 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 142

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 1

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 5

South Asian (SAS) AF: 0.00 AC: 0 AN: 505

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 95

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome AF: 0.000354 AC: 38 AN: 107260 Hom.: 0 Cov.: 19 AF XY: 0.000232 AC XY: 7 AN XY: 30158

African (AFR) AF: 0.0000676 AC: 2 AN: 29581

American (AMR) AF: 0.00145 AC: 15 AN: 10342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2614

East Asian (EAS) AF: 0.00 AC: 0 AN: 3274

South Asian (SAS) AF: 0.00 AC: 0 AN: 2334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5353

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.000408 AC: 21 AN: 51469

Other (OTH) AF: 0.00 AC: 0 AN: 1463

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.000306

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	-0.61
CADD	Benign	18
DANN	Benign	0.77
PhyloP100		0.31
PromoterAI		-0.026	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1013945435; hg19: chrX-135229797;