rs61754871

Variant names:

• chr17-75840236-T-C
• rs61754871
• NM_199242.3:c.847A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-75840236-T-C
• chr17-75840236-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_199242.3(UNC13D):​c.847A>G​(p.Ile283Val) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,613,934 control chromosomes in the GnomAD database, including 36 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I283L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (14 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.82
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007616967).
• BP6: Variant 17-75840236-T-C is Benign according to our data. Variant chr17-75840236-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00789 (1201/152250) while in subpopulation AFR AF = 0.0272 (1130/41526). AF 95% confidence interval is 0.0259. There are 22 homozygotes in GnomAd4. There are 561 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.847A>G	p.Ile283Val	missense	Exon 10 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.847A>G	p.Ile283Val	missense	Exon 10 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.847A>G	p.Ile283Val	missense	Exon 10 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.847A>G	p.Ile283Val	missense	Exon 11 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1197 AN: 152132 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00194 AC: 485 AN: 250474 AF XY: 0.00141

Gnomad AFR exome AF: 0.0254

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000761 AC: 1113 AN: 1461684 Hom.: 14 Cov.: 34 AF XY: 0.000657 AC XY: 478 AN XY: 727156

African (AFR) AF: 0.0256 AC: 857 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111996

Other (OTH) AF: 0.00225 AC: 136 AN: 60394

GnomAD4 genome AF: 0.00789 AC: 1201 AN: 152250 Hom.: 22 Cov.: 32 AF XY: 0.00753 AC XY: 561 AN XY: 74460

African (AFR) AF: 0.0272 AC: 1130 AN: 41526

American (AMR) AF: 0.00346 AC: 53 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00259 Hom.: 9

Bravo AF: 0.00863

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00250 AC: 304

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Benign	0.016
Eigen_PC	Benign	0.087
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.16
Sift	Uncertain	0.020	D
Sift4G	Benign	0.13	T
Polyphen		0.37	B
Vest4		0.65
MVP		0.81
MPC		0.25
ClinPred		0.0067	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.14
Mutation Taster		=95/5	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: rs61754871; hg19: chr17-73836317; COSMIC: COSV104392539;