16-4340943-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016069.11(PAM16):​c.268G>A​(p.Gly90Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PAM16
NM_016069.11 missense

Scores

8
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49
Variant links:
Genes affected
PAM16 (HGNC:29679): (presequence translocase associated motor 16) This gene encodes a mitochondrial protein involved in granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. This protein also plays a role in the import of nuclear-encoded mitochondrial proteins into the mitochondrial matrix and may be important in reactive oxygen species (ROS) homeostasis. Mutations in this gene cause Megarbane-Dagher-Melike type spondylometaphyseal dysplasia, an early lethal skeletal dysplasia characterized by short stature, developmental delay and other skeletal abnormalities. [provided by RefSeq, May 2017]
CORO7-PAM16 (HGNC:44424): (CORO7-PAM16 readthrough) This locus represents naturally occurring read-through transcription between the neighboring CORO7 (coronin 7) and PAM16 (presequence translocase-associated motor 16) genes on chromosome 16. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jan 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAM16NM_016069.11 linkc.268G>A p.Gly90Ser missense_variant Exon 4 of 5 ENST00000318059.8 NP_057153.8 Q9Y3D7
CORO7-PAM16NM_001201479.2 linkc.3037G>A p.Gly1013Ser missense_variant Exon 30 of 31 NP_001188408.1 A0A0A6YYL4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAM16ENST00000318059.8 linkc.268G>A p.Gly90Ser missense_variant Exon 4 of 5 1 NM_016069.11 ENSP00000315693.3 Q9Y3D7
CORO7-PAM16ENST00000572467.5 linkc.3037G>A p.Gly1013Ser missense_variant Exon 30 of 31 2 ENSP00000460885.1 A0A0A6YYL4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461358
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726932
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:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Nov 23, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with PAM16-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 90 of the PAM16 protein (p.Gly90Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
.;T;.;.;.;T;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Pathogenic
3.6
.;H;.;.;.;H;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-6.0
.;D;.;.;.;.;.
REVEL
Uncertain
0.56
Sift
Uncertain
0.0020
.;D;.;.;.;.;.
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D
Polyphen
0.99
.;D;.;.;.;D;.
Vest4
0.95
MutPred
0.89
Gain of disorder (P = 0.0412);Gain of disorder (P = 0.0412);.;.;.;Gain of disorder (P = 0.0412);.;
MVP
0.91
MPC
0.43, 0.48
ClinPred
0.99
D
GERP RS
6.2
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.75
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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: rs2053634799; hg19: chr16-4390944; API