NM_199242.3:c.567C>T

Variant names:

• chr17-75842435-G-A
• rs147903551
• NM_199242.3:c.567C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_199242.3(UNC13D):​c.567C>T​(p.Ile189Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. I189I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UNC13D NM_199242.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.2217
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.350
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 17-75842435-G-A is Benign according to our data. Variant chr17-75842435-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2758161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.35 with no splicing effect.

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.567C>T	p.Ile189Ile	splice_region synonymous	Exon 6 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.567C>T	p.Ile189Ile	splice_region synonymous	Exon 6 of 32	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.567C>T	p.Ile189Ile	splice_region synonymous	Exon 6 of 33	ENSP00000388093.1
	UNC13D	ENST00000592386.6	TSL:5	c.549C>T	p.Ile183Ile	splice_region synonymous	Exon 6 of 11	ENSP00000466826.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Sep 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.86
PhyloP100		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.22
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.10		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: rs147903551; hg19: chr17-73838516; COSMIC: COSV99256282; COSMIC: COSV99256282;