4-1814530-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_012318.3(LETM1):​c.2114G>A​(p.Ser705Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

LETM1
NM_012318.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65
Variant links:
Genes affected
LETM1 (HGNC:6556): (leucine zipper and EF-hand containing transmembrane protein 1) This gene encodes a protein that is localized to the inner mitochondrial membrane. The protein functions to maintain the mitochondrial tubular shapes and is required for normal mitochondrial morphology and cellular viability. Mutations in this gene cause Wolf-Hirschhorn syndrome, a complex malformation syndrome caused by the deletion of parts of the distal short arm of chromosome 4. Related pseudogenes have been identified on chromosomes 8, 15 and 19. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.104602784).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000643 (94/1461530) while in subpopulation NFE AF= 0.0000738 (82/1111838). AF 95% confidence interval is 0.0000606. There are 0 homozygotes in gnomad4_exome. There are 46 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LETM1NM_012318.3 linkc.2114G>A p.Ser705Asn missense_variant Exon 14 of 14 ENST00000302787.3 NP_036450.1 O95202-1
LETM1XM_006713884.2 linkc.2111G>A p.Ser704Asn missense_variant Exon 14 of 14 XP_006713947.1
LETM1XM_047415673.1 linkc.1571G>A p.Ser524Asn missense_variant Exon 13 of 13 XP_047271629.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LETM1ENST00000302787.3 linkc.2114G>A p.Ser705Asn missense_variant Exon 14 of 14 1 NM_012318.3 ENSP00000305653.2 O95202-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152278
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
249278
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000446
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000643
AC:
94
AN:
1461530
Hom.:
0
Cov.:
32
AF XY:
0.0000633
AC XY:
46
AN XY:
727016
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:
0.0000738
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152278
Hom.:
0
Cov.:
34
AF XY:
0.0000269
AC XY:
2
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2114G>A (p.S705N) alteration is located in exon 14 (coding exon 14) of the LETM1 gene. This alteration results from a G to A substitution at nucleotide position 2114, causing the serine (S) at amino acid position 705 to be replaced by an asparagine (N). 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
Benign
0.084
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.0038
T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.10
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.85
D
M_CAP
Benign
0.0029
T
MetaRNN
Benign
0.10
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
M
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.51
N
REVEL
Benign
0.033
Sift
Benign
0.17
T
Sift4G
Benign
0.34
T
Polyphen
0.0030
B
Vest4
0.12
MutPred
0.11
Loss of glycosylation at S705 (P = 0.0563);
MVP
0.69
MPC
0.39
ClinPred
0.083
T
GERP RS
4.0
Varity_R
0.032
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: -5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs765944262; hg19: chr4-1816257; API