NM_001009996.3:c.1033G>T

Variant names:

• chr3-49016642-C-A
• rs2093078379
• NM_001009996.3:c.1033G>T

Variant summary

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

The NM_001009996.3(DALRD3):​c.1033G>T​(p.Ala345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A345V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DALRD3 NM_001009996.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.705
• Publications: 0 publications found

Genes affected

DALRD3 (HGNC:25536): (DALR anticodon binding domain containing 3) The exact function of this gene is not known. It encodes a protein with a DALR anticodon binding domain similar to that of class Ia aminoacyl tRNA synthetases. This gene is located in a cluster of genes (with a complex sense-anti-sense genome architecture) on chromosome 3, and contains two micro RNA (miRNA) precursors (mir-425 and mir-191) in one of its introns. Preferential expression of this gene (the miRNAs and other genes in the cluster) in testis suggests a role of this gene in spermatogenesis (PMID:19906709). [provided by RefSeq, Feb 2013]

DALRD3 Gene-Disease associations (from GenCC):

• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• developmental and epileptic encephalopathy, 86

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)

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=0.047041208).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009996.3. 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
	DALRD3	NM_001009996.3	MANE Select	c.1033G>T	p.Ala345Ser	missense	Exon 7 of 12	NP_001009996.1	Q5D0E6-1
	DALRD3	NM_001276405.2		c.1033G>T	p.Ala345Ser	missense	Exon 7 of 12	NP_001263334.1	Q5D0E6-2
	DALRD3	NM_018114.6		c.532G>T	p.Ala178Ser	missense	Exon 7 of 12	NP_060584.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DALRD3	ENST00000341949.9	TSL:1 MANE Select	c.1033G>T	p.Ala345Ser	missense	Exon 7 of 12	ENSP00000344989.4	Q5D0E6-1
	DALRD3	ENST00000441576.6	TSL:1	c.1033G>T	p.Ala345Ser	missense	Exon 7 of 12	ENSP00000410623.2	Q5D0E6-2
	DALRD3	ENST00000440857.5	TSL:1	c.532G>T	p.Ala178Ser	missense	Exon 8 of 12	ENSP00000403770.1	C9JJG6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441022 Hom.: 0 Cov.: 36 AF XY: 0.00000140 AC XY: 1 AN XY: 714228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 43504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24304

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 82626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100238

Other (OTH) AF: 0.00 AC: 0 AN: 59486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.70
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.014
Sift	Benign	0.26	T
Sift4G	Benign	0.14	T
Polyphen		0.13	B
Vest4		0.24
MutPred		0.38		Gain of disorder (P = 0.0165)
MVP		0.31
MPC		0.17
ClinPred		0.13	T
GERP RS		1.9
PromoterAI		0.014	Neutral
Varity_R		0.068
gMVP		0.14
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2093078379; hg19: chr3-49054075;