NM_001286451.2:c.414G>A

Variant names:

• chr15-90931401-C-T
• rs117318472
• NM_001286451.2:c.414G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001286451.2(HDDC3):​c.414G>A​(p.Trp138*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00512 in 1,582,088 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (21 hom.)
• Consequence: HDDC3 NM_001286451.2 stop_gained
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.84
• Publications: 4 publications found

Genes affected

HDDC3 (HGNC:30522): (HD domain containing 3) Predicted to enable guanosine-3',5'-bis(diphosphate) 3'-diphosphatase activity. [provided by Alliance of Genome Resources, Apr 2022]

UNC45A (HGNC:30594): (unc-45 myosin chaperone A) This gene encodes a regulatory component of the progesterone receptor/heat shock protein 90 chaperoning complex, which functions in the assembly and folding of the progesterone receptor. The encoded protein is thought to be essential for normal cell proliferation, and for the accumulation of myosin during development of muscle cells. [provided by RefSeq, Sep 2018]

UNC45A Gene-Disease associations (from GenCC):

• osteootohepatoenteric syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 15-90931401-C-T is Benign according to our data. Variant chr15-90931401-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2645716.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286451.2. 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
	HDDC3	NM_001286451.2	MANE Select	c.414G>A	p.Trp138*	stop_gained	Exon 4 of 4	NP_001273380.1	Q8N4P3-1
	HDDC3	NM_198527.4		c.*142G>A		3_prime_UTR	Exon 4 of 4	NP_940929.1	Q8N4P3-2
	UNC45A	NM_001039675.2		c.-760+1146C>T		intron	N/A	NP_001034764.1	Q9H3U1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDDC3	ENST00000394272.8	TSL:2 MANE Select	c.414G>A	p.Trp138*	stop_gained	Exon 4 of 4	ENSP00000377814.4	Q8N4P3-1
	HDDC3	ENST00000559898.5	TSL:1	c.*280G>A		3_prime_UTR	Exon 3 of 3	ENSP00000454103.1	H0YNP9
	HDDC3	ENST00000330334.7	TSL:1	c.*142G>A		3_prime_UTR	Exon 4 of 4	ENSP00000330721.3	Q8N4P3-2

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152154 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00287 AC: 585 AN: 203856 AF XY: 0.00287

Gnomad AFR exome AF: 0.000700

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000213

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00556

Gnomad OTH exome AF: 0.00241

GnomAD4 exome AF: 0.00530 AC: 7582 AN: 1429816 Hom.: 21 Cov.: 31 AF XY: 0.00511 AC XY: 3623 AN XY: 708756

African (AFR) AF: 0.000803 AC: 26 AN: 32390

American (AMR) AF: 0.00169 AC: 66 AN: 39146

Ashkenazi Jewish (ASJ) AF: 0.000467 AC: 12 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 37406

South Asian (SAS) AF: 0.000350 AC: 29 AN: 82878

European-Finnish (FIN) AF: 0.00212 AC: 110 AN: 51988

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5738

European-Non Finnish (NFE) AF: 0.00647 AC: 7086 AN: 1095302

Other (OTH) AF: 0.00415 AC: 246 AN: 59258

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152272 Hom.: 7 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74456

African (AFR) AF: 0.00113 AC: 47 AN: 41560

American (AMR) AF: 0.00157 AC: 24 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00610 AC: 415 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00442 Hom.: 5

Bravo AF: 0.00328

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00597 AC: 23

ExAC AF: 0.00266 AC: 320

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		6.8
Vest4		0.20
GERP RS		4.5
Mutation Taster		=114/86	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117318472; hg19: chr15-91474631;