NM_199242.3:c.888G>C

Variant names:

• chr17-75840081-C-G
• rs7223416
• NM_199242.3:c.888G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_199242.3(UNC13D):​c.888G>C​(p.Pro296Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,612,518 control chromosomes in the GnomAD database, including 107,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P296P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.45 (19147 hom., cov: 33)
  • Exomes 𝑓: 0.34 (88338 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.608
• Publications: 25 publications found

Genes affected

UNC13D (HGNC:23147): (unc-13 homolog D) This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]

UNC13D Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-75840081-C-G is Benign according to our data. Variant chr17-75840081-C-G is described in ClinVar as Benign. ClinVar VariationId is 263247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.608 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199242.3. 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
	UNC13D	NM_199242.3	MANE Select	c.888G>C	p.Pro296Pro	synonymous	Exon 11 of 32	NP_954712.1	Q70J99-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.888G>C	p.Pro296Pro	synonymous	Exon 11 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000965711.1		c.940G>C	p.Glu314Gln	missense	Exon 12 of 33	ENSP00000635770.1
	UNC13D	ENST00000412096.6	TSL:2	c.888G>C	p.Pro296Pro	synonymous	Exon 11 of 33	ENSP00000388093.1	Q70J99-3

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68989 AN: 151982 Hom.: 19097 Cov.: 33

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.354 AC: 87671 AN: 247578 AF XY: 0.352

Gnomad AFR exome AF: 0.803

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.419

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.338 AC: 493094 AN: 1460418 Hom.: 88338 Cov.: 57 AF XY: 0.338 AC XY: 245594 AN XY: 726504

African (AFR) AF: 0.807 AC: 26996 AN: 33468

American (AMR) AF: 0.259 AC: 11538 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10383 AN: 26086

East Asian (EAS) AF: 0.429 AC: 17001 AN: 39660

South Asian (SAS) AF: 0.363 AC: 31266 AN: 86202

European-Finnish (FIN) AF: 0.239 AC: 12624 AN: 52778

Middle Eastern (MID) AF: 0.494 AC: 2818 AN: 5706

European-Non Finnish (NFE) AF: 0.322 AC: 358248 AN: 1111602

Other (OTH) AF: 0.368 AC: 22220 AN: 60316

GnomAD4 genome AF: 0.454 AC: 69089 AN: 152100 Hom.: 19147 Cov.: 33 AF XY: 0.446 AC XY: 33137 AN XY: 74348

African (AFR) AF: 0.788 AC: 32703 AN: 41522

American (AMR) AF: 0.321 AC: 4898 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1423 AN: 3472

East Asian (EAS) AF: 0.418 AC: 2150 AN: 5148

South Asian (SAS) AF: 0.350 AC: 1689 AN: 4822

European-Finnish (FIN) AF: 0.238 AC: 2516 AN: 10584

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22366 AN: 67952

Other (OTH) AF: 0.454 AC: 958 AN: 2112

Alfa AF: 0.313 Hom.: 2330

Bravo AF: 0.478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Familial hemophagocytic lymphohistiocytosis 3 (4)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7223416; hg19: chr17-73836162; COSMIC: COSV52884004; COSMIC: COSV52884004;