2-135641647-A-C

Variant names:

• chr2-135641647-A-C
• rs748980855
• NM_001378107.1:c.1331A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378107.1(R3HDM1):​c.1331A>C​(p.Tyr444Ser) 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 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y444C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: R3HDM1 NM_001378107.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18
• Publications: 0 publications found

Genes affected

R3HDM1 (HGNC:9757): (R3H domain containing 1) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000308733 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378107.1. 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
	R3HDM1	NM_001378107.1	MANE Select	c.1331A>C	p.Tyr444Ser	missense	Exon 15 of 27	NP_001365036.1	A0A804HIA8
	R3HDM1	NM_001282798.2		c.1331A>C	p.Tyr444Ser	missense	Exon 15 of 26	NP_001269727.1	Q15032-3
	R3HDM1	NM_001354200.2		c.1331A>C	p.Tyr444Ser	missense	Exon 15 of 26	NP_001341129.1	Q15032-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	R3HDM1	ENST00000683871.1	MANE Select	c.1331A>C	p.Tyr444Ser	missense	Exon 15 of 27	ENSP00000506980.1	A0A804HIA8
	R3HDM1	ENST00000264160.8	TSL:1	c.1331A>C	p.Tyr444Ser	missense	Exon 15 of 26	ENSP00000264160.4	Q15032-1
	R3HDM1	ENST00000409478.5	TSL:1	c.1087+2525A>C		intron	N/A	ENSP00000386457.1	Q15032-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461888 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.14
Sift	Benign	0.27	T
Sift4G	Benign	0.36	T
Polyphen		0.96	P
Vest4		0.67
MutPred		0.31		Gain of glycosylation at Y444 (P = 0.0062)
MVP		0.60
MPC		0.36
ClinPred		0.77	D
GERP RS		5.8
Varity_R		0.27
gMVP		0.63
Mutation Taster		=76/24	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: rs748980855; hg19: chr2-136399217;