chrX-136147571-C-T

Variant names:

• chrX-136147571-C-T
• rs777858178
• NM_001159702.3:c.-158C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001159702.3(FHL1):​c.-158C>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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (100 hom., 738 hem., cov: 20)
  • Exomes 𝑓: 0.0012 (0 hom. 0 hem.)
• Consequence: FHL1 NM_001159702.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.233
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-136147571-C-T is Benign according to our data. Variant chrX-136147571-C-T is described in ClinVar as [Benign]. Clinvar id is 1281259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.-158C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159702.3	c.-158C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.-158C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000394155.8	c.-158C>T		5_prime_UTR_variant	Exon 1 of 8	5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 2987 AN: 107993 Hom.: 99 Cov.: 20

Gnomad AFR AF: 0.0944

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000787

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000466

Gnomad OTH AF: 0.0276

GnomAD4 exome AF: 0.00123 AC: 2 AN: 1624 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 690

African (AFR) AF: 0.118 AC: 2 AN: 17

American (AMR) AF: 0.00 AC: 0 AN: 5

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7

East Asian (EAS) AF: 0.00 AC: 0 AN: 37

South Asian (SAS) AF: 0.00 AC: 0 AN: 636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 871

Other (OTH) AF: 0.00 AC: 0 AN: 36

GnomAD4 genome AF: 0.0277 AC: 2992 AN: 108034 Hom.: 100 Cov.: 20 AF XY: 0.0236 AC XY: 738 AN XY: 31232

African (AFR) AF: 0.0944 AC: 2826 AN: 29941

American (AMR) AF: 0.00956 AC: 100 AN: 10463

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2603

East Asian (EAS) AF: 0.00 AC: 0 AN: 3327

South Asian (SAS) AF: 0.000790 AC: 2 AN: 2531

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5303

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 209

European-Non Finnish (NFE) AF: 0.000466 AC: 24 AN: 51543

Other (OTH) AF: 0.0272 AC: 40 AN: 1469

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		-0.23
PromoterAI		0.071	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs777858178; hg19: chrX-135229730; COSMIC: COSV65781112; COSMIC: COSV65781112;