NM_199242.3:c.1228A>C

Variant names:

• chr17-75836642-T-G
• rs117221419
• NM_199242.3:c.1228A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_199242.3(UNC13D):​c.1228A>C​(p.Ile410Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,613,688 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I410T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.12
• Publications: 5 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 -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_199242.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.00644204).
• BP6: Variant 17-75836642-T-G is Benign according to our data. Variant chr17-75836642-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225510.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000532 (81/152206) while in subpopulation EAS AF = 0.0147 (76/5184). AF 95% confidence interval is 0.012. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.1228A>C	p.Ile410Leu	missense	Exon 14 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.1228A>C	p.Ile410Leu	missense	Exon 14 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.1228A>C	p.Ile410Leu	missense	Exon 14 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.1228A>C	p.Ile410Leu	missense	Exon 15 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152088 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00119 AC: 298 AN: 250852 AF XY: 0.00102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0159

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000351 AC: 513 AN: 1461482 Hom.: 5 Cov.: 37 AF XY: 0.000323 AC XY: 235 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0116 AC: 460 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111998

Other (OTH) AF: 0.000414 AC: 25 AN: 60390

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152206 Hom.: 1 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74444

African (AFR) AF: 0.00 AC: 0 AN: 41520

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.0147 AC: 76 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000491 Hom.: 1

Bravo AF: 0.000638

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Familial hemophagocytic lymphohistiocytosis 3 (3)
-	1	-	Autoinflammatory syndrome (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.70
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.48	N
PhyloP100		1.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.080	N
REVEL	Pathogenic	0.67
Sift	Benign	1.0	T
Sift4G	Benign	0.33	T
Polyphen		0.019	B
Vest4		0.39
MVP		0.48
MPC		0.096
ClinPred		0.028	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.24
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs117221419; hg19: chr17-73832723; COSMIC: COSV52886737; COSMIC: COSV52886737;