16-4340357-G-T

Position:

• chr16-4340357-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000318059.8(PAM16):​c.340C>A​(p.Gln114Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,612,836 control chromosomes in the GnomAD database, including 4,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q114E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.094 (921 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3204 hom.)
• Consequence: PAM16 ENST00000318059.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.96

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014361143).
• BP6: Variant 16-4340357-G-T is Benign according to our data. Variant chr16-4340357-G-T is described in ClinVar as [Benign]. Clinvar id is 1279559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAM16	NM_016069.11	c.340C>A	p.Gln114Lys	missense_variant	5/5	ENST00000318059.8	NP_057153.8
CORO7-PAM16	NM_001201479.2	c.3109C>A	p.Gln1037Lys	missense_variant	31/31		NP_001188408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAM16	ENST00000318059.8	c.340C>A	p.Gln114Lys	missense_variant	5/5	1	NM_016069.11	ENSP00000315693	P1

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14322 AN: 152174 Hom.: 924 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.0990

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0903

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0875

GnomAD3 exomes AF: 0.0757 AC: 18908 AN: 249762 Hom.: 931 AF XY: 0.0757 AC XY: 10257 AN XY: 135554

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.0659

Gnomad ASJ exome AF: 0.0620

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0851

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.0678

GnomAD4 exome AF: 0.0585 AC: 85396 AN: 1460544 Hom.: 3204 Cov.: 33 AF XY: 0.0600 AC XY: 43574 AN XY: 726570

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.0707

Gnomad4 ASJ exome AF: 0.0610

Gnomad4 EAS exome AF: 0.0998

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.0814

Gnomad4 NFE exome AF: 0.0464

Gnomad4 OTH exome AF: 0.0719

GnomAD4 genome AF: 0.0941 AC: 14327 AN: 152292 Hom.: 921 Cov.: 33 AF XY: 0.0957 AC XY: 7124 AN XY: 74468

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0827

Gnomad4 ASJ AF: 0.0651

Gnomad4 EAS AF: 0.0988

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0903

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0880

Alfa AF: 0.0560 Hom.: 610

Bravo AF: 0.0958

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0501 AC: 193

ESP6500AA AF: 0.161 AC: 708

ESP6500EA AF: 0.0480 AC: 413

ExAC AF: 0.0766 AC: 9268

Asia WGS AF: 0.126 AC: 440 AN: 3478

EpiCase AF: 0.0520

EpiControl AF: 0.0516

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.032	T;.;.;.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.78	D
MetaRNN	Benign	0.0014	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N;.;.;.;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.47	N;.;.;.;.;.
REVEL	Benign	0.052
Sift	Benign	0.50	T;.;.;.;.;.
Sift4G	Benign	0.66	T;T;T;T;T;T
Polyphen		0.0040	B;.;.;.;B;.
Vest4		0.096
MPC		0.17
ClinPred		0.0069	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs11989; hg19: chr16-4390358; COSMIC: COSV52109762; COSMIC: COSV52109762;