chr16-4340958-C-G

Variant names:

• chr16-4340958-C-G
• rs1260237933
• NM_016069.11:c.253G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016069.11(PAM16):​c.253G>C​(p.Asp85His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,368 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: 0.0000014 (0 hom.)
• Consequence: PAM16 NM_016069.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM16	NM_016069.11	c.253G>C	p.Asp85His	missense_variant	Exon 4 of 5	ENST00000318059.8	NP_057153.8
CORO7-PAM16	NM_001201479.2	c.3022G>C	p.Asp1008His	missense_variant	Exon 30 of 31		NP_001188408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAM16	ENST00000318059.8	c.253G>C	p.Asp85His	missense_variant	Exon 4 of 5	1	NM_016069.11	ENSP00000315693.3
CORO7-PAM16	ENST00000572467.5	c.3022G>C	p.Asp1008His	missense_variant	Exon 30 of 31	2		ENSP00000460885.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250780 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461368 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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 specified Uncertain:1

Jan 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3022G>C (p.D1008H) alteration is located in exon 30 (coding exon 30) of the CORO7-PAM16 gene. This alteration results from a G to C substitution at nucleotide position 3022, causing the aspartic acid (D) at amino acid position 1008 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.;.;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	.;M;.;.;.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	.;D;.;.;.;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	.;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;D;.
Vest4		0.81
MutPred		0.78		Gain of MoRF binding (P = 0.0428);Gain of MoRF binding (P = 0.0428);.;.;.;Gain of MoRF binding (P = 0.0428);.;
MVP		0.75
MPC		0.63, 0.53
ClinPred		0.98	D
GERP RS		6.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.87
gMVP		0.88

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

Other links and lift over

dbSNP: rs1260237933; hg19: chr16-4390959;