17-75828040-T-C

Variant names:

• chr17-75828040-T-C
• rs7210574
• NM_199242.3:c.3198A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_199242.3(UNC13D):​c.3198A>G​(p.Glu1066Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,579,720 control chromosomes in the GnomAD database, including 118,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (22524 hom., cov: 33)
  • Exomes 𝑓: 0.35 (95548 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.0140
• Publications: 31 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 17-75828040-T-C is Benign according to our data. Variant chr17-75828040-T-C is described in ClinVar as Benign. ClinVar VariationId is 263240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.862 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.3198A>G	p.Glu1066Glu	synonymous	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.3198A>G	p.Glu1066Glu	synonymous	Exon 32 of 32	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.3198A>G	p.Glu1066Glu	synonymous	Exon 32 of 33	ENSP00000388093.1
	UNC13D	ENST00000868100.1		c.3198A>G	p.Glu1066Glu	synonymous	Exon 33 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74087 AN: 152058 Hom.: 22457 Cov.: 33

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.385 AC: 73388 AN: 190804 AF XY: 0.381

Gnomad AFR exome AF: 0.888

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.497

Gnomad EAS exome AF: 0.436

Gnomad FIN exome AF: 0.276

Gnomad NFE exome AF: 0.343

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.353 AC: 503670 AN: 1427544 Hom.: 95548 Cov.: 62 AF XY: 0.353 AC XY: 249594 AN XY: 707378

African (AFR) AF: 0.897 AC: 29316 AN: 32688

American (AMR) AF: 0.304 AC: 12055 AN: 39700

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 12605 AN: 25518

East Asian (EAS) AF: 0.461 AC: 17351 AN: 37674

South Asian (SAS) AF: 0.379 AC: 31121 AN: 82040

European-Finnish (FIN) AF: 0.276 AC: 13808 AN: 49952

Middle Eastern (MID) AF: 0.523 AC: 2933 AN: 5606

European-Non Finnish (NFE) AF: 0.330 AC: 361148 AN: 1095400

Other (OTH) AF: 0.396 AC: 23333 AN: 58966

GnomAD4 genome AF: 0.488 AC: 74205 AN: 152176 Hom.: 22524 Cov.: 33 AF XY: 0.479 AC XY: 35629 AN XY: 74382

African (AFR) AF: 0.869 AC: 36137 AN: 41564

American (AMR) AF: 0.338 AC: 5162 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1732 AN: 3472

East Asian (EAS) AF: 0.441 AC: 2277 AN: 5162

South Asian (SAS) AF: 0.361 AC: 1739 AN: 4812

European-Finnish (FIN) AF: 0.276 AC: 2921 AN: 10592

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22880 AN: 67968

Other (OTH) AF: 0.460 AC: 971 AN: 2110

Alfa AF: 0.386 Hom.: 9368

Bravo AF: 0.515

Asia WGS AF: 0.432 AC: 1500 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Familial hemophagocytic lymphohistiocytosis 3 (4)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.6
DANN	Benign	0.82
PhyloP100		0.014
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs7210574; hg19: chr17-73824121; COSMIC: COSV52882840; COSMIC: COSV52882840;