NM_199242.3:c.3198A>C

Variant names:

• chr17-75828040-T-G
• rs7210574
• NM_199242.3:c.3198A>C

Variant summary

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

The NM_199242.3(UNC13D):​c.3198A>C​(p.Glu1066Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1066E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• Publications: 31 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.3198A>C	p.Glu1066Asp	missense	Exon 32 of 32	NP_954712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.3198A>C	p.Glu1066Asp	missense	Exon 32 of 32	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.3198A>C	p.Glu1066Asp	missense	Exon 32 of 33	ENSP00000388093.1
	UNC13D	ENST00000699510.1		c.2064A>C	p.Glu688Asp	missense	Exon 20 of 20	ENSP00000514405.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 9368

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.073
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.014
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.042	D
Polyphen		0.99	D
Vest4		0.10
MutPred		0.29		Loss of helix (P = 0.028)
MVP		0.67
MPC		0.099
ClinPred		0.96	D
GERP RS		3.0
Varity_R		0.14
gMVP		0.49

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: rs7210574; hg19: chr17-73824121;