chr17-75830089-C-T

Variant names:

• chr17-75830089-C-T
• rs144744401
• NM_199242.3:c.2893G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_199242.3(UNC13D):​c.2893G>A​(p.Ala965Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,580,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. A965D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.94
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017514974).
• BP6: Variant 17-75830089-C-T is Benign according to our data. Variant chr17-75830089-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582747.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000571 (87/152284) while in subpopulation NFE AF = 0.00112 (76/68036). AF 95% confidence interval is 0.000915. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2893G>A	p.Ala965Thr	missense	Exon 30 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.2893G>A	p.Ala965Thr	missense	Exon 30 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2893G>A	p.Ala965Thr	missense	Exon 30 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2893G>A	p.Ala965Thr	missense	Exon 31 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00112

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000473 AC: 92 AN: 194524 AF XY: 0.000490

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0000707

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000594

GnomAD4 exome AF: 0.00108 AC: 1549 AN: 1428504 Hom.: 0 Cov.: 31 AF XY: 0.00107 AC XY: 756 AN XY: 707284

African (AFR) AF: 0.000213 AC: 7 AN: 32898

American (AMR) AF: 0.000102 AC: 4 AN: 39192

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25400

East Asian (EAS) AF: 0.00 AC: 0 AN: 38214

South Asian (SAS) AF: 0.00 AC: 0 AN: 81450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51016

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.00136 AC: 1490 AN: 1095420

Other (OTH) AF: 0.000777 AC: 46 AN: 59190

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74460

African (AFR) AF: 0.000144 AC: 6 AN: 41532

American (AMR) AF: 0.000261 AC: 4 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000797 Hom.: 0

Bravo AF: 0.000570

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000283 AC: 34

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Familial hemophagocytic lymphohistiocytosis 3 (3)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.086
Sift	Benign	0.24	T
Sift4G	Benign	0.45	T
Polyphen		0.031	B
Vest4		0.13
MVP		0.69
MPC		0.097
ClinPred		0.010	T
GERP RS		4.3
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.050
gMVP		0.22
Mutation Taster		=90/10	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: rs144744401; hg19: chr17-73826170; COSMIC: COSV104392650;