NM_199242.3:c.1977C>T

Variant names:

• chr17-75834935-G-A
• rs2290770
• NM_199242.3:c.1977C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_199242.3(UNC13D):​c.1977C>T​(p.Thr659Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,026 control chromosomes in the GnomAD database, including 2,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (259 hom., cov: 33)
  • Exomes 𝑓: 0.012 (1788 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00
• Publications: 12 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 17-75834935-G-A is Benign according to our data. Variant chr17-75834935-G-A is described in ClinVar as Benign. ClinVar VariationId is 263220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.1977C>T	p.Thr659Thr	synonymous	Exon 21 of 32	NP_954712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.1977C>T	p.Thr659Thr	synonymous	Exon 21 of 32	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.1977C>T	p.Thr659Thr	synonymous	Exon 21 of 33	ENSP00000388093.1
	UNC13D	ENST00000699510.1		c.843C>T	p.Thr281Thr	synonymous	Exon 9 of 20	ENSP00000514405.1

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4159 AN: 152126 Hom.: 259 Cov.: 33

Gnomad AFR AF: 0.0511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0302 AC: 7581 AN: 251390 AF XY: 0.0282

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.285

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0124 AC: 18167 AN: 1461782 Hom.: 1788 Cov.: 34 AF XY: 0.0126 AC XY: 9143 AN XY: 727186

African (AFR) AF: 0.0505 AC: 1691 AN: 33480

American (AMR) AF: 0.00371 AC: 166 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26136

East Asian (EAS) AF: 0.283 AC: 11236 AN: 39700

South Asian (SAS) AF: 0.0212 AC: 1825 AN: 86258

European-Finnish (FIN) AF: 0.0149 AC: 794 AN: 53326

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.00112 AC: 1247 AN: 1112008

Other (OTH) AF: 0.0192 AC: 1160 AN: 60384

GnomAD4 genome AF: 0.0273 AC: 4153 AN: 152244 Hom.: 259 Cov.: 33 AF XY: 0.0295 AC XY: 2195 AN XY: 74432

African (AFR) AF: 0.0509 AC: 2115 AN: 41542

American (AMR) AF: 0.00883 AC: 135 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.276 AC: 1429 AN: 5176

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4824

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68012

Other (OTH) AF: 0.0209 AC: 44 AN: 2110

Alfa AF: 0.00790 Hom.: 60

Bravo AF: 0.0301

Asia WGS AF: 0.118 AC: 409 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.4
DANN	Benign	0.77
PhyloP100		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs2290770; hg19: chr17-73831016; COSMIC: COSV52883519; COSMIC: COSV52883519;