rs546262142

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018100.4(EFHC1):​c.1147C>A​(p.Pro383Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P383S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

10
6
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.48
Variant links:
Genes affected
EFHC1 (HGNC:16406): (EF-hand domain containing 1) This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EFHC1NM_018100.4 linkc.1147C>A p.Pro383Thr missense_variant Exon 7 of 11 ENST00000371068.11 NP_060570.2 Q5JVL4-1B2CKC5
EFHC1NM_001172420.2 linkc.1090C>A p.Pro364Thr missense_variant Exon 8 of 12 NP_001165891.1 Q5JVL4-3B2CKC5
EFHC1NR_033327.2 linkn.2473C>A non_coding_transcript_exon_variant Exon 6 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EFHC1ENST00000371068.11 linkc.1147C>A p.Pro383Thr missense_variant Exon 7 of 11 1 NM_018100.4 ENSP00000360107.4 Q5JVL4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461696
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727142
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.33
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T;.;.;D;T;T;T;T;T;.;T;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP
Uncertain
0.093
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Pathogenic
3.3
.;.;.;M;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-6.8
.;.;.;D;.;.;.;.;.;.;.;.;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0030
.;.;.;D;.;.;.;.;.;.;.;.;D
Sift4G
Uncertain
0.013
.;.;.;D;.;.;.;.;.;.;.;.;D
Polyphen
1.0
.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4
0.92, 0.89
MutPred
0.66
.;.;.;Gain of glycosylation at P383 (P = 0.0352);Gain of glycosylation at P383 (P = 0.0352);Gain of glycosylation at P383 (P = 0.0352);Gain of glycosylation at P383 (P = 0.0352);Gain of glycosylation at P383 (P = 0.0352);.;Gain of glycosylation at P383 (P = 0.0352);.;.;.;
MVP
0.92
MPC
0.49
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.71
gMVP
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: chr6-52334140; API