X-136209921-G-C

Variant names:

• chrX-136209921-G-C
• NM_001159699.2:c.787G>C

Variant summary

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

The NM_001159699.2(FHL1):​c.787G>C​(p.Asp263His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76

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_001159699.2	c.787G>C	p.Asp263His	missense_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1
FHL1	NM_001159702.3	c.939G>C	p.Thr313Thr	synonymous_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000370683.6	c.787G>C	p.Asp263His	missense_variant	Exon 6 of 6	1	NM_001159699.2	ENSP00000359717.1
FHL1	ENST00000394155.8	c.939G>C	p.Thr313Thr	synonymous_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098151 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363509

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	.;.;.;.;.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;.;.;.;.;D;D;D;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
PROVEAN	Benign	-0.92	.;N;.;N;N;N;N;N;N;.
REVEL	Uncertain	0.48
Sift	Benign	0.65	.;T;.;T;T;T;T;T;T;.
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T
Vest4		0.57
MutPred		0.44		.;.;.;.;.;.;Loss of solvent accessibility (P = 0.1473);.;.;.;
MVP		0.98
ClinPred		0.52	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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-135292080;