2-85356880-CAAAA-CAAA

Variant names:

• chr2-85356880-CA-C
• rs759699457
• NM_001135022.2:c.-232-72delA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001135022.2(ELMOD3):​c.-232-72delA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.20 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELMOD3 NM_001135022.2 intron
• Clinical Significance: Likely 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-85356880-CA-C is Benign according to our data. Variant chr2-85356880-CA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1316665.Status of the report is criteria_provided_single_submitter, 1 stars.

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.-232-72delA		intron	N/A	NP_001128494.1	Q96FG2-1
	ELMOD3	NM_032213.5		c.-232-72delA		intron	N/A	NP_115589.2
	ELMOD3	NM_001135021.2		c.-232-72delA		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.-232-72delA		intron	N/A	ENSP00000387139.3	Q96FG2-1
	ELMOD3	ENST00000315658.11	TSL:1	c.-232-72delA		intron	N/A	ENSP00000318264.7	Q96FG2-6
	ELMOD3	ENST00000393852.8	TSL:1	c.-232-72delA		intron	N/A	ENSP00000377434.4	Q96FG2-1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 374 AN: 124800 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00164

Gnomad EAS AF: 0.00338

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00397

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00357

GnomAD4 exome AF: 0.199 AC: 2919 AN: 14668 Hom.: 0 Cov.: 0 AF XY: 0.200 AC XY: 1522 AN XY: 7594

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

African (AFR) AF: 0.168 AC: 78 AN: 464

American (AMR) AF: 0.189 AC: 91 AN: 482

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 125 AN: 634

East Asian (EAS) AF: 0.197 AC: 181 AN: 920

South Asian (SAS) AF: 0.198 AC: 143 AN: 724

European-Finnish (FIN) AF: 0.184 AC: 86 AN: 468

Middle Eastern (MID) AF: 0.184 AC: 14 AN: 76

European-Non Finnish (NFE) AF: 0.201 AC: 1996 AN: 9922

Other (OTH) AF: 0.210 AC: 205 AN: 978

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00303 AC: 378 AN: 124818 Hom.: 0 Cov.: 32 AF XY: 0.00321 AC XY: 192 AN XY: 59858

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

African (AFR) AF: 0.00140 AC: 48 AN: 34316

American (AMR) AF: 0.00472 AC: 58 AN: 12294

Ashkenazi Jewish (ASJ) AF: 0.00164 AC: 5 AN: 3054

East Asian (EAS) AF: 0.00340 AC: 15 AN: 4416

South Asian (SAS) AF: 0.00150 AC: 6 AN: 3994

European-Finnish (FIN) AF: 0.0148 AC: 104 AN: 7022

Middle Eastern (MID) AF: 0.00439 AC: 1 AN: 228

European-Non Finnish (NFE) AF: 0.00235 AC: 134 AN: 57030

Other (OTH) AF: 0.00413 AC: 7 AN: 1694

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000644 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely 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

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: rs759699457; hg19: chr2-85584003;