16-4513004-G-T

Variant names:

• chr16-4513004-G-T
• rs767541693
• NM_013399.3:c.302C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013399.3(CDIP1):​c.302C>A​(p.Thr101Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000126 in 1,590,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T101M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CDIP1 NM_013399.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• Publications: 1 publications found

Genes affected

CDIP1 (HGNC:13234): (cell death inducing p53 target 1) Predicted to enable metal ion binding activity. Acts upstream of or within intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator and tumor necrosis factor-mediated signaling pathway. Located in cytoplasmic side of late endosome membrane; cytoplasmic side of lysosomal membrane; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09642464).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013399.3. 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
	CDIP1	NM_013399.3	MANE Select	c.302C>A	p.Thr101Lys	missense	Exon 5 of 6	NP_037531.2	Q9H305-1
	CDIP1	NM_001199054.2		c.302C>A	p.Thr101Lys	missense	Exon 5 of 6	NP_001185983.1	Q9H305-1
	CDIP1	NM_001199055.2		c.242-57C>A		intron	N/A	NP_001185984.1	Q9H305-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDIP1	ENST00000567695.6	TSL:1 MANE Select	c.302C>A	p.Thr101Lys	missense	Exon 5 of 6	ENSP00000457877.1	Q9H305-1
	CDIP1	ENST00000399599.7	TSL:1	c.302C>A	p.Thr101Lys	missense	Exon 4 of 5	ENSP00000382508.2	Q9H305-1
	CDIP1	ENST00000563332.6	TSL:1	c.302C>A	p.Thr101Lys	missense	Exon 5 of 6	ENSP00000454994.1	Q9H305-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000983 AC: 2 AN: 203502 AF XY: 0.00

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.95e-7 AC: 1 AN: 1437916 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 713132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 40262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25526

East Asian (EAS) AF: 0.00 AC: 0 AN: 38856

South Asian (SAS) AF: 0.00 AC: 0 AN: 82632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101442

Other (OTH) AF: 0.00 AC: 0 AN: 59514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.36
Sift	Benign	0.35	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.40
MutPred		0.32		Gain of methylation at T101 (P = 2e-04)
MVP		0.29
MPC		0.24
ClinPred		0.13	T
GERP RS		6.0
Varity_R		0.20
gMVP		0.52

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: rs767541693; hg19: chr16-4563005;