X-136207151-T-C

Variant names:

• chrX-136207151-T-C
• NM_001159702.3:c.292T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001159699.2(FHL1):​c.340T>C​(p.Ser114Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.292T>C	p.Ser98Pro	missense_variant	Exon 4 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.340T>C	p.Ser114Pro	missense_variant	Exon 3 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.292T>C	p.Ser98Pro	missense_variant	Exon 4 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.340T>C	p.Ser114Pro	missense_variant	Exon 3 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Mar 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.292T>C (p.S98P) alteration is located in exon 4 (coding exon 2) of the FHL1 gene. This alteration results from a T to C substitution at nucleotide position 292, causing the serine (S) at amino acid position 98 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;.;T;.;T;T;T;.;.;T;.;T;.;.;T;.;T;D;.;.;.;T;T;.
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.93	.;D;.;D;D;D;D;D;D;.;.;.;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.2	M;M;M;.;M;.;.;.;.;M;.;M;.;M;M;.;.;.;M;.;.;.;.;.;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.6	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.043	D;T;D;T;T;T;T;T;T;D;T;D;T;D;D;T;T;T;T;T;T;T;T;D;D
Polyphen		0.80, 0.58	.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;P;.;.
Vest4		0.54
MutPred		0.46		Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);.;.;.;Loss of phosphorylation at S98 (P = 0.0522);Loss of phosphorylation at S98 (P = 0.0522);
MVP		0.98
MPC		1.2
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135289310;