16-4340323-G-A

Position:

chr16-4340323-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000318059.8(PAM16):c.374C>T(p.Thr125Met) variant causes a missense change. The variant allele was found at a frequency of 0.000189 in 1,612,472 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

PAM16
ENST00000318059.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.07

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]

PAM16 links:

CORO7-PAM16 (HGNC:):

CORO7-PAM16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27396283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAM16	NM_016069.11 linkuse as main transcript	c.374C>T	p.Thr125Met	missense_variant	5/5	ENST00000318059.8	NP_057153.8
CORO7-PAM16	NM_001201479.2 linkuse as main transcript	c.3143C>T	p.Thr1048Met	missense_variant	31/31		NP_001188408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAM16	ENST00000318059.8 linkuse as main transcript	c.374C>T	p.Thr125Met	missense_variant	5/5	1	NM_016069.11	ENSP00000315693	P1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000224

AC:

AN:

249756

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000240

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000187

AC:

273

AN:

1460184

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

726312

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000203

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000204

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000282

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000182

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2021

The c.3143C>T (p.T1048M) alteration is located in exon 31 (coding exon 31) of the CORO7-PAM16 gene. This alteration results from a C to T substitution at nucleotide position 3143, causing the threonine (T) at amino acid position 1048 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the PAM16 protein (p.Thr125Met). This variant is present in population databases (rs148571756, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with PAM16-related conditions. ClinVar contains an entry for this variant (Variation ID: 1494233). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

T;.;.;.;T;.

Eigen

Benign

-0.060

Eigen_PC

Benign

0.043

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

L;.;.;.;L;.

MutationTaster

Benign

0.99

N;D;D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.1

N;.;.;.;.;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.14

B;.;.;.;B;.

Vest4

0.63

MVP

0.74

MPC

0.61

ClinPred

0.16

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.52

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over