chr2-85363163-C-T

Variant names:

• chr2-85363163-C-T
• rs7564372
• NM_001135022.2:c.196C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001135022.2(ELMOD3):​c.196C>T​(p.Arg66Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,601,340 control chromosomes in the GnomAD database, including 1,544 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.062 (563 hom., cov: 32)
  • Exomes 𝑓: 0.028 (981 hom.)
• Consequence: ELMOD3 NM_001135022.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0310
• Publications: 11 publications found

Genes affected

ELMOD3 (HGNC:26158): (ELMO domain containing 3) This gene encodes a member of the engulfment and cell motility family of GTPase-activating proteins that regulate Arf GTPase proteins. Members of this family are defined by a conserved engulfment and cell motility domain. In rat cochlea, the encoded protein is found in stereocilia, kinocilia and cuticular plate of developing hair cells suggesting a function for this protein in cochlear sensory cells. An allelic variant of this family has been associated with autosomal recessive nonsyndromic deafness-88 in humans. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ELMOD3 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 88

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001386553).
• BP6: Variant 2-85363163-C-T is Benign according to our data. Variant chr2-85363163-C-T is described in ClinVar as Benign. ClinVar VariationId is 508136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135022.2. 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
	ELMOD3	NM_001135022.2	MANE Select	c.196C>T	p.Arg66Cys	missense	Exon 6 of 14	NP_001128494.1	Q96FG2-1
	ELMOD3	NM_032213.5		c.196C>T	p.Arg66Cys	missense	Exon 4 of 11	NP_115589.2
	ELMOD3	NM_001135021.2		c.196C>T	p.Arg66Cys	missense	Exon 7 of 15	NP_001128493.1	Q96FG2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELMOD3	ENST00000409013.8	TSL:1 MANE Select	c.196C>T	p.Arg66Cys	missense	Exon 6 of 14	ENSP00000387139.3	Q96FG2-1
	ELMOD3	ENST00000315658.11	TSL:1	c.196C>T	p.Arg66Cys	missense	Exon 4 of 11	ENSP00000318264.7	Q96FG2-6
	ELMOD3	ENST00000393852.8	TSL:1	c.196C>T	p.Arg66Cys	missense	Exon 5 of 13	ENSP00000377434.4	Q96FG2-1

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9424 AN: 152116 Hom.: 559 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0295 AC: 7390 AN: 250122 AF XY: 0.0258

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0284 AC: 41170 AN: 1449106 Hom.: 981 Cov.: 27 AF XY: 0.0272 AC XY: 19609 AN XY: 721786

African (AFR) AF: 0.168 AC: 5546 AN: 33106

American (AMR) AF: 0.0212 AC: 947 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0273 AC: 712 AN: 26036

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39652

South Asian (SAS) AF: 0.00659 AC: 566 AN: 85824

European-Finnish (FIN) AF: 0.0317 AC: 1695 AN: 53388

Middle Eastern (MID) AF: 0.0290 AC: 167 AN: 5752

European-Non Finnish (NFE) AF: 0.0269 AC: 29592 AN: 1100722

Other (OTH) AF: 0.0324 AC: 1942 AN: 59974

GnomAD4 genome AF: 0.0620 AC: 9444 AN: 152234 Hom.: 563 Cov.: 32 AF XY: 0.0593 AC XY: 4411 AN XY: 74444

African (AFR) AF: 0.159 AC: 6584 AN: 41510

American (AMR) AF: 0.0315 AC: 481 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4818

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0269 AC: 1830 AN: 68024

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0313 Hom.: 477

Bravo AF: 0.0678

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.160 AC: 704

ESP6500EA AF: 0.0263 AC: 226

ExAC AF: 0.0320 AC: 3889

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0274

EpiControl AF: 0.0274

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.031
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.041
Sift	Benign	0.049	D
Sift4G	Benign	0.069	T
Polyphen		0.52	P
Vest4		0.19
MPC		0.62
ClinPred		0.013	T
GERP RS		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs7564372; hg19: chr2-85590286; COSMIC: COSV59774845; COSMIC: COSV59774845;