2-85356880-CAAAA-CAAAAAA

Variant names:

• chr2-85356880-C-CAA
• rs759699457
• NM_001135022.2:c.-232-73_-232-72dupAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001135022.2(ELMOD3):​c.-232-73_-232-72dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0318 in 139,854 control chromosomes in the GnomAD database, including 168 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.035 (168 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (0 hom.)
• Consequence: ELMOD3 NM_001135022.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.706
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 2-85356880-C-CAA is Benign according to our data. Variant chr2-85356880-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 1262264.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.-232-73_-232-72dupAA		intron	N/A	NP_001128494.1	Q96FG2-1
	ELMOD3	NM_032213.5		c.-232-73_-232-72dupAA		intron	N/A	NP_115589.2
	ELMOD3	NM_001135021.2		c.-232-73_-232-72dupAA		intron	N/A	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.-232-73_-232-72dupAA		intron	N/A	ENSP00000387139.3	Q96FG2-1
	ELMOD3	ENST00000315658.11	TSL:1	c.-232-73_-232-72dupAA		intron	N/A	ENSP00000318264.7	Q96FG2-6
	ELMOD3	ENST00000393852.8	TSL:1	c.-232-73_-232-72dupAA		intron	N/A	ENSP00000377434.4	Q96FG2-1

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 4342 AN: 125056 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.00359

Gnomad EAS AF: 0.0684

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00267

Gnomad MID AF: 0.00388

Gnomad NFE AF: 0.000629

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.00616 AC: 91 AN: 14780 Hom.: 0 Cov.: 0 AF XY: 0.00536 AC XY: 41 AN XY: 7650

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

African (AFR) AF: 0.0466 AC: 22 AN: 472

American (AMR) AF: 0.0165 AC: 8 AN: 486

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 1 AN: 638

East Asian (EAS) AF: 0.0173 AC: 16 AN: 924

South Asian (SAS) AF: 0.00275 AC: 2 AN: 728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 78

European-Non Finnish (NFE) AF: 0.00330 AC: 33 AN: 9994

Other (OTH) AF: 0.00913 AC: 9 AN: 986

⚠️ 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 AF: 0.0348 AC: 4350 AN: 125074 Hom.: 168 Cov.: 32 AF XY: 0.0347 AC XY: 2085 AN XY: 60018

African (AFR) AF: 0.103 AC: 3548 AN: 34286

American (AMR) AF: 0.0315 AC: 388 AN: 12310

Ashkenazi Jewish (ASJ) AF: 0.00359 AC: 11 AN: 3060

East Asian (EAS) AF: 0.0688 AC: 304 AN: 4416

South Asian (SAS) AF: 0.00125 AC: 5 AN: 3996

European-Finnish (FIN) AF: 0.00267 AC: 19 AN: 7116

Middle Eastern (MID) AF: 0.00427 AC: 1 AN: 234

European-Non Finnish (NFE) AF: 0.000630 AC: 36 AN: 57184

Other (OTH) AF: 0.0223 AC: 38 AN: 1702

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs759699457; hg19: chr2-85584003;