16-4340357-G-T

Variant names:

• chr16-4340357-G-T
• rs11989
• NM_016069.11:c.340C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016069.11(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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 NM_016069.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.96
• Publications: 16 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016069.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAM16	NM_016069.11	MANE Select	c.340C>A	p.Gln114Lys	missense	Exon 5 of 5	NP_057153.8
	CORO7-PAM16	NM_001201479.2		c.3109C>A	p.Gln1037Lys	missense	Exon 31 of 31	NP_001188408.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAM16	ENST00000318059.8	TSL:1 MANE Select	c.340C>A	p.Gln114Lys	missense	Exon 5 of 5	ENSP00000315693.3	Q9Y3D7
	CORO7-PAM16	ENST00000572467.5	TSL:2	c.3109C>A	p.Gln1037Lys	missense	Exon 31 of 31	ENSP00000460885.1
	PAM16	ENST00000573236.5	TSL:1	n.596C>A		non_coding_transcript_exon	Exon 4 of 4

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

GnomAD2 exomes AF: 0.0757 AC: 18908 AN: 249762 AF XY: 0.0757

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 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

African (AFR) AF: 0.169 AC: 5659 AN: 33480

American (AMR) AF: 0.0707 AC: 3162 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0610 AC: 1594 AN: 26132

East Asian (EAS) AF: 0.0998 AC: 3961 AN: 39698

South Asian (SAS) AF: 0.119 AC: 10256 AN: 86256

European-Finnish (FIN) AF: 0.0814 AC: 4259 AN: 52290

Middle Eastern (MID) AF: 0.102 AC: 588 AN: 5760

European-Non Finnish (NFE) AF: 0.0464 AC: 51579 AN: 1111864

Other (OTH) AF: 0.0719 AC: 4338 AN: 60356

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

African (AFR) AF: 0.174 AC: 7223 AN: 41548

American (AMR) AF: 0.0827 AC: 1265 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3472

East Asian (EAS) AF: 0.0988 AC: 512 AN: 5182

South Asian (SAS) AF: 0.127 AC: 610 AN: 4814

European-Finnish (FIN) AF: 0.0903 AC: 959 AN: 10626

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0481 AC: 3274 AN: 68030

Other (OTH) AF: 0.0880 AC: 186 AN: 2114

Alfa AF: 0.0643 Hom.: 1259

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.78	D
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
PhyloP100		3.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.052
Sift	Benign	0.50	T
Sift4G	Benign	0.66	T
Polyphen		0.0040	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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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