rs3744011

Variant names:

• chr17-75844191-C-T
• rs3744011
• NM_199242.3:c.117+30G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-75844191-C-T
• chr17-75844191-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):​c.117+30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,607,184 control chromosomes in the GnomAD database, including 6,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1327 hom., cov: 32)
  • Exomes 𝑓: 0.061 (5089 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.57
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Laboratory for Molecular Medicine
• 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 (BayesDel_noAF=-0.8).
• BP6: Variant 17-75844191-C-T is Benign according to our data. Variant chr17-75844191-C-T is described in ClinVar as Benign. ClinVar VariationId is 263211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

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.117+30G>A		intron	N/A	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.117+30G>A		intron	N/A	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.117+30G>A		intron	N/A	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.117+30G>A		intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15837 AN: 152088 Hom.: 1328 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0598

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0494

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0947

GnomAD2 exomes AF: 0.0857 AC: 20959 AN: 244680 AF XY: 0.0851

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0531

Gnomad EAS exome AF: 0.318

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0721

GnomAD4 exome AF: 0.0612 AC: 89064 AN: 1454978 Hom.: 5089 Cov.: 31 AF XY: 0.0628 AC XY: 45445 AN XY: 724104

African (AFR) AF: 0.214 AC: 7173 AN: 33442

American (AMR) AF: 0.0323 AC: 1442 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 1393 AN: 26118

East Asian (EAS) AF: 0.324 AC: 12855 AN: 39690

South Asian (SAS) AF: 0.119 AC: 10237 AN: 86240

European-Finnish (FIN) AF: 0.0481 AC: 2293 AN: 47714

Middle Eastern (MID) AF: 0.0937 AC: 538 AN: 5744

European-Non Finnish (NFE) AF: 0.0437 AC: 48562 AN: 1111020

Other (OTH) AF: 0.0758 AC: 4571 AN: 60304

GnomAD4 genome AF: 0.104 AC: 15842 AN: 152206 Hom.: 1327 Cov.: 32 AF XY: 0.106 AC XY: 7900 AN XY: 74426

African (AFR) AF: 0.206 AC: 8550 AN: 41504

American (AMR) AF: 0.0597 AC: 914 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3472

East Asian (EAS) AF: 0.307 AC: 1584 AN: 5154

South Asian (SAS) AF: 0.121 AC: 582 AN: 4814

European-Finnish (FIN) AF: 0.0494 AC: 525 AN: 10626

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3252 AN: 68018

Other (OTH) AF: 0.0928 AC: 196 AN: 2112

Alfa AF: 0.0684 Hom.: 269

Bravo AF: 0.111

Asia WGS AF: 0.190 AC: 660 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.80
DANN	Benign	0.66
PhyloP100		-3.6
PromoterAI		0.0076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3744011;

hg19: chr17-73840272;

COSMIC: COSV52885816;

COSMIC: COSV52885816;