NM_199242.3:c.3248A>C

Variant names:

• chr17-75827990-T-G
• rs766632931
• NM_199242.3:c.3248A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_199242.3(UNC13D):​c.3248A>C​(p.Gln1083Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,603,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. Q1083E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.32
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25353593).

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.3248A>C	p.Gln1083Pro	missense	Exon 32 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.3248A>C	p.Gln1083Pro	missense	Exon 32 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000868100.1		c.3248A>C	p.Gln1083Pro	missense	Exon 33 of 33	ENSP00000538159.1
	UNC13D	ENST00000868101.1		c.3248A>C	p.Gln1083Pro	missense	Exon 33 of 33	ENSP00000538160.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 33

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000267 AC: 6 AN: 224620 AF XY: 0.0000406

Gnomad AFR exome AF: 0.00

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: 0.0000610

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000154 AC: 224 AN: 1451568 Hom.: 0 Cov.: 31 AF XY: 0.000141 AC XY: 102 AN XY: 721496

African (AFR) AF: 0.00 AC: 0 AN: 33210

American (AMR) AF: 0.00 AC: 0 AN: 43832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39160

South Asian (SAS) AF: 0.00 AC: 0 AN: 84834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.000202 AC: 224 AN: 1108464

Other (OTH) AF: 0.00 AC: 0 AN: 59784

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000832 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hemophagocytic lymphohistiocytosis 3 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		0.63	P
Vest4		0.37
MutPred		0.19		Gain of glycosylation at Q1083 (P = 0.027)
MVP		0.77
MPC		0.17
ClinPred		0.21	T
GERP RS		4.3
Varity_R		0.38
gMVP		0.53
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs766632931; hg19: chr17-73824071;