rs150952348

Variant names:

• chr17-75828078-T-C
• rs150952348
• NM_199242.3:c.3160A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-75828078-T-C
• chr17-75828078-T-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BS1_Supporting

The NM_199242.3(UNC13D):​c.3160A>G​(p.Ile1054Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,573,552 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.458
• Publications: 7 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_199242.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.007429898).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000782 (119/152092) while in subpopulation NFE AF = 0.00128 (87/67944). AF 95% confidence interval is 0.00106. There are 1 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.3160A>G	p.Ile1054Val	missense	Exon 32 of 32	NP_954712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.3160A>G	p.Ile1054Val	missense	Exon 32 of 32	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.3160A>G	p.Ile1054Val	missense	Exon 32 of 33	ENSP00000388093.1
	UNC13D	ENST00000868100.1		c.3160A>G	p.Ile1054Val	missense	Exon 33 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.000783 AC: 119 AN: 151974 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0000655

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: 0.00128

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000520 AC: 95 AN: 182704 AF XY: 0.000549

Gnomad AFR exome AF: 0.000284

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000205

GnomAD4 exome AF: 0.000927 AC: 1317 AN: 1421460 Hom.: 1 Cov.: 33 AF XY: 0.000930 AC XY: 654 AN XY: 703532

African (AFR) AF: 0.0000919 AC: 3 AN: 32652

American (AMR) AF: 0.000104 AC: 4 AN: 38582

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 37606

South Asian (SAS) AF: 0.00 AC: 0 AN: 81272

European-Finnish (FIN) AF: 0.000442 AC: 22 AN: 49722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00116 AC: 1264 AN: 1091648

Other (OTH) AF: 0.000391 AC: 23 AN: 58872

GnomAD4 genome AF: 0.000782 AC: 119 AN: 152092 Hom.: 1 Cov.: 33 AF XY: 0.000726 AC XY: 54 AN XY: 74374

African (AFR) AF: 0.0000482 AC: 2 AN: 41504

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 67944

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.173 Hom.: 6355

Bravo AF: 0.000771

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000268 AC: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.2
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.46
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.070
Sift	Benign	0.27	T
Sift4G	Benign	0.067	T
Polyphen		0.0	B
Vest4		0.055
MVP		0.42
MPC		0.082
ClinPred		0.030	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.27
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150952348; hg19: chr17-73824159; COSMIC: COSV104392719;