16-50066449-G-A

Variant names:

• chr16-50066449-G-A
• rs969347139
• NM_182922.4:c.221G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182922.4(HEATR3):​c.221G>A​(p.Gly74Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,241,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G74V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: HEATR3 NM_182922.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.491
• Publications: 0 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-AS1 (HGNC:55406): (HEATR3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044365257).

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.221G>A	p.Gly74Asp	missense	Exon 2 of 15	NP_891552.1	Q7Z4Q2-1
	HEATR3	NM_001329729.2		c.-472G>A		5_prime_UTR	Exon 2 of 16	NP_001316658.1
	HEATR3	NM_001329730.2		c.-446G>A		5_prime_UTR	Exon 2 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.221G>A	p.Gly74Asp	missense	Exon 2 of 15	ENSP00000299192.7	Q7Z4Q2-1
	HEATR3	ENST00000887924.1		c.221G>A	p.Gly74Asp	missense	Exon 2 of 15	ENSP00000557983.1
	HEATR3	ENST00000887923.1		c.221G>A	p.Gly74Asp	missense	Exon 2 of 14	ENSP00000557982.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000322 AC: 4 AN: 1241760 Hom.: 0 Cov.: 33 AF XY: 0.00000496 AC XY: 3 AN XY: 605322

African (AFR) AF: 0.00 AC: 0 AN: 25050

American (AMR) AF: 0.00 AC: 0 AN: 12218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17756

East Asian (EAS) AF: 0.00 AC: 0 AN: 28786

South Asian (SAS) AF: 0.00 AC: 0 AN: 56854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4846

European-Non Finnish (NFE) AF: 0.00000394 AC: 4 AN: 1014660

Other (OTH) AF: 0.00 AC: 0 AN: 51134

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.1
DANN	Benign	0.94
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.49
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.024
Sift	Benign	0.64	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.30		Loss of MoRF binding (P = 0.0469)
MVP		0.27
MPC		0.26
ClinPred		0.15	T
GERP RS		-3.4
PromoterAI		-0.34	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.50
Mutation Taster		=97/3	polymorphism

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: rs969347139; hg19: chr16-50100360; COSMIC: COSV53529960; COSMIC: COSV53529960;