16-4340948-A-G

Position:

• chr16-4340948-A-G

Variant summary

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

The ENST00000318059.8(PAM16):​c.263T>C​(p.Val88Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAM16 ENST00000318059.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.85

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:):

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/exons	MANE	Protein	UniProt
PAM16	NM_016069.11	c.263T>C	p.Val88Ala	missense_variant	4/5	ENST00000318059.8	NP_057153.8
CORO7-PAM16	NM_001201479.2	c.3032T>C	p.Val1011Ala	missense_variant	30/31		NP_001188408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAM16	ENST00000318059.8	c.263T>C	p.Val88Ala	missense_variant	4/5	1	NM_016069.11	ENSP00000315693	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461366 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726938

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2021

This sequence change replaces valine with alanine at codon 88 of the PAM16 protein (p.Val88Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PAM16-related conditions. 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 tolerated. 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	0.093
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;T;.;.;.;T;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.89	.;L;.;.;.;L;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.050	.;N;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.61	.;T;.;.;.;.;.
Sift4G	Benign	0.29	T;T;T;T;T;T;T
Polyphen		0.0030	.;B;.;.;.;B;.
Vest4		0.60
MutPred		0.45		Loss of stability (P = 0.0335);Loss of stability (P = 0.0335);.;.;.;Loss of stability (P = 0.0335);.;
MVP		0.42
MPC		0.16, 0.28
ClinPred		0.78	D
GERP RS		6.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.085
gMVP		0.71

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: chr16-4390949;