chr16-50070178-T-C

Variant names:

• chr16-50070178-T-C
• rs1184398890
• NM_182922.4:c.400T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_182922.4(HEATR3):​c.400T>C​(p.Cys134Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000145 in 1,375,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HEATR3 NM_182922.4 missense, splice_region
• Scores: Splicing: ADA: 0.9006
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.56
• Publications: 3 publications found

Genes affected

HEATR3 (HGNC:26087): (HEAT repeat containing 3) The protein encoded by this gene plays a role in ribosomal protein transport and in the assembly of the 5S ribonucleoprotein particle (5S RNP). The encoded protein also may be involved in NOD2-mediated NF-kappaB signaling. [provided by RefSeq, Jul 2016]

HEATR3 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 21

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• PP5: Variant 16-50070178-T-C is Pathogenic according to our data. Variant chr16-50070178-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1300197.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182922.4. 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
	HEATR3	NM_182922.4	MANE Select	c.400T>C	p.Cys134Arg	missense splice_region	Exon 4 of 15	NP_891552.1	Q7Z4Q2-1
	HEATR3	NM_001329729.2		c.49T>C	p.Cys17Arg	missense splice_region	Exon 5 of 16	NP_001316658.1
	HEATR3	NM_001329730.2		c.49T>C	p.Cys17Arg	missense splice_region	Exon 5 of 16	NP_001316659.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEATR3	ENST00000299192.8	TSL:1 MANE Select	c.400T>C	p.Cys134Arg	missense splice_region	Exon 4 of 15	ENSP00000299192.7	Q7Z4Q2-1
	HEATR3	ENST00000887924.1		c.400T>C	p.Cys134Arg	missense splice_region	Exon 4 of 15	ENSP00000557983.1
	HEATR3	ENST00000887923.1		c.400T>C	p.Cys134Arg	missense splice_region	Exon 4 of 14	ENSP00000557982.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243514 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1375316 Hom.: 0 Cov.: 20 AF XY: 0.00000145 AC XY: 1 AN XY: 687846

African (AFR) AF: 0.00 AC: 0 AN: 31744

American (AMR) AF: 0.00 AC: 0 AN: 42786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 38864

South Asian (SAS) AF: 0.00 AC: 0 AN: 81142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1039226

Other (OTH) AF: 0.00 AC: 0 AN: 57392

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Diamond-Blackfan anemia 1 (1)
1	-	-	Diamond-Blackfan anemia 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.54		Gain of disorder (P = 0.0222)
MVP		0.81
MPC		0.97
ClinPred		0.93	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.59
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.14		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: rs1184398890; hg19: chr16-50104089;