2-135636088-A-G

Variant names:

• chr2-135636088-A-G
• rs961360
• NM_001378107.1:c.808A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378107.1(R3HDM1):​c.808A>G​(p.Met270Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.174 in 1,612,386 control chromosomes in the GnomAD database, including 32,766 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3955 hom., cov: 32)
  • Exomes 𝑓: 0.17 (28811 hom.)
• Consequence: R3HDM1 NM_001378107.1 missense, splice_region
• Scores: Splicing: ADA: 0.0009339
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.97
• Publications: 51 publications found

Genes affected

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026819408).
• BP6: Variant 2-135636088-A-G is Benign according to our data. Variant chr2-135636088-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 4076126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDM1	NM_001378107.1	c.808A>G	p.Met270Val	missense_variant, splice_region_variant	Exon 11 of 27	ENST00000683871.1	NP_001365036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDM1	ENST00000683871.1	c.808A>G	p.Met270Val	missense_variant, splice_region_variant	Exon 11 of 27		NM_001378107.1	ENSP00000506980.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32005 AN: 152032 Hom.: 3937 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.243 AC: 60808 AN: 250266 AF XY: 0.244

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.461

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.170 AC: 247737 AN: 1460236 Hom.: 28811 Cov.: 32 AF XY: 0.176 AC XY: 128026 AN XY: 726434

African (AFR) AF: 0.215 AC: 7190 AN: 33388

American (AMR) AF: 0.303 AC: 13474 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 11941 AN: 26032

East Asian (EAS) AF: 0.468 AC: 18522 AN: 39546

South Asian (SAS) AF: 0.300 AC: 25813 AN: 86028

European-Finnish (FIN) AF: 0.167 AC: 8906 AN: 53350

Middle Eastern (MID) AF: 0.379 AC: 2180 AN: 5754

European-Non Finnish (NFE) AF: 0.132 AC: 146569 AN: 1111300

Other (OTH) AF: 0.218 AC: 13142 AN: 60302

GnomAD4 genome AF: 0.211 AC: 32070 AN: 152150 Hom.: 3955 Cov.: 32 AF XY: 0.217 AC XY: 16110 AN XY: 74382

African (AFR) AF: 0.203 AC: 8443 AN: 41526

American (AMR) AF: 0.291 AC: 4445 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1638 AN: 3470

East Asian (EAS) AF: 0.456 AC: 2353 AN: 5162

South Asian (SAS) AF: 0.307 AC: 1478 AN: 4818

European-Finnish (FIN) AF: 0.161 AC: 1703 AN: 10594

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11173 AN: 67990

Other (OTH) AF: 0.279 AC: 588 AN: 2110

Alfa AF: 0.201 Hom.: 14653

Bravo AF: 0.220

TwinsUK AF: 0.125 AC: 465

ALSPAC AF: 0.121 AC: 466

ESP6500AA AF: 0.199 AC: 877

ESP6500EA AF: 0.175 AC: 1508

ExAC AF: 0.240 AC: 29102

Asia WGS AF: 0.375 AC: 1301 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.0074	.;T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	.;D;D;D;D
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	.;N;.;.;N
PhyloP100		7.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.57	N;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.33	T;T;T;.;T
Sift4G	Benign	0.37	T;T;T;T;T
Polyphen		0.93	.;P;.;.;.
Vest4		0.13
MPC		0.25
ClinPred		0.047	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.22
Mutation Taster		=64/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00093
dbscSNV1_RF	Benign	0.0040
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: rs961360; hg19: chr2-136393658; COSMIC: COSV51520564; COSMIC: COSV51520564;