15-40740176-C-T

Variant names:

• chr15-40740176-C-T
• rs989225061
• NM_018145.3:c.928G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018145.3(RMDN3):​c.928G>A​(p.Ala310Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RMDN3 NM_018145.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.624

Genes affected

RMDN3 (HGNC:25550): (regulator of microtubule dynamics 3) Enables microtubule binding activity. Involved in cellular calcium ion homeostasis. Located in several cellular components, including intercellular bridge; mitochondrial outer membrane; and spindle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07128066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMDN3	NM_018145.3	c.928G>A	p.Ala310Thr	missense_variant	Exon 7 of 13	ENST00000338376.8	NP_060615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMDN3	ENST00000338376.8	c.928G>A	p.Ala310Thr	missense_variant	Exon 7 of 13	1	NM_018145.3	ENSP00000342493.3
RMDN3	ENST00000558777.5	n.*479G>A		non_coding_transcript_exon_variant	Exon 8 of 14	2		ENSP00000453357.1
RMDN3	ENST00000558777.5	n.*479G>A		3_prime_UTR_variant	Exon 8 of 14	2		ENSP00000453357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459378 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726082

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.928G>A (p.A310T) alteration is located in exon 7 (coding exon 6) of the RMDN3 gene. This alteration results from a G to A substitution at nucleotide position 928, causing the alanine (A) at amino acid position 310 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.027	T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.81	N;N;N
REVEL	Benign	0.041
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.30
MutPred		0.35		Gain of phosphorylation at A310 (P = 0.04);Gain of phosphorylation at A310 (P = 0.04);.;
MVP		0.37
MPC		0.15
ClinPred		0.25	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs989225061; hg19: chr15-41032374;