16-4340913-C-A

Variant names:

• chr16-4340913-C-A
• rs142976385
• NM_016069.11:c.291+7G>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_016069.11(PAM16):​c.291+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,612,938 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (35 hom.)
• Consequence: PAM16 NM_016069.11 splice_region, intron
• Scores: Splicing: ADA: 0.0008855
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.354

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-4340913-C-A is Benign according to our data. Variant chr16-4340913-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 789224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAM16	NM_016069.11	c.291+7G>T		splice_region_variant, intron_variant	Intron 4 of 4	ENST00000318059.8	NP_057153.8
CORO7-PAM16	NM_001201479.2	c.3060+7G>T		splice_region_variant, intron_variant	Intron 30 of 30		NP_001188408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAM16	ENST00000318059.8	c.291+7G>T		splice_region_variant, intron_variant	Intron 4 of 4	1	NM_016069.11	ENSP00000315693.3
CORO7-PAM16	ENST00000572467.5	c.3060+7G>T		splice_region_variant, intron_variant	Intron 30 of 30	2		ENSP00000460885.1

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 644 AN: 152094 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00718

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00390 AC: 979 AN: 250954 Hom.: 3 AF XY: 0.00395 AC XY: 536 AN XY: 135778

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.00598

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00572 AC: 8354 AN: 1460728 Hom.: 35 Cov.: 32 AF XY: 0.00558 AC XY: 4051 AN XY: 726614

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.00664

Gnomad4 OTH exome AF: 0.00480

GnomAD4 genome AF: 0.00422 AC: 643 AN: 152210 Hom.: 1 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74438

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00716

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00621 Hom.: 2

Bravo AF: 0.00387

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PAM16: BP4, BS2 -

PAM16-related disorder Benign:1

Aug 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.2
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00089
dbscSNV1_RF	Benign	0.026
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: rs142976385; hg19: chr16-4390914;