chr2-85356880-C-CA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001135022.2(ELMOD3):​c.-232-72dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 139,756 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (7 hom., cov: 32)
  • Exomes 𝑓: 0.088 (0 hom.)
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-85356880-C-CA is Benign according to our data. Variant chr2-85356880-C-CA is described in ClinVar as Likely_benign. ClinVar VariationId is 1316699.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00879 (1098/124938) while in subpopulation AFR AF = 0.025 (858/34318). AF 95% confidence interval is 0.0236. There are 7 homozygotes in GnomAd4. There are 561 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1087 AN: 124920 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00488

Gnomad ASJ AF: 0.000328

Gnomad EAS AF: 0.00226

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00382

Gnomad MID AF: 0.00391

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00593

GnomAD4 exome AF: 0.0881 AC: 1306 AN: 14818 Hom.: 0 Cov.: 0 AF XY: 0.0876 AC XY: 672 AN XY: 7670

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

African (AFR) AF: 0.110 AC: 52 AN: 472

American (AMR) AF: 0.0602 AC: 29 AN: 482

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 65 AN: 638

East Asian (EAS) AF: 0.0892 AC: 83 AN: 930

South Asian (SAS) AF: 0.0579 AC: 42 AN: 726

European-Finnish (FIN) AF: 0.0879 AC: 42 AN: 478

Middle Eastern (MID) AF: 0.115 AC: 9 AN: 78

European-Non Finnish (NFE) AF: 0.0901 AC: 903 AN: 10026

Other (OTH) AF: 0.0820 AC: 81 AN: 988

⚠️ 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: 0.00879 AC: 1098 AN: 124938 Hom.: 7 Cov.: 32 AF XY: 0.00936 AC XY: 561 AN XY: 59938

African (AFR) AF: 0.0250 AC: 858 AN: 34318

American (AMR) AF: 0.00487 AC: 60 AN: 12312

Ashkenazi Jewish (ASJ) AF: 0.000328 AC: 1 AN: 3050

East Asian (EAS) AF: 0.00226 AC: 10 AN: 4416

South Asian (SAS) AF: 0.000751 AC: 3 AN: 3996

European-Finnish (FIN) AF: 0.00382 AC: 27 AN: 7066

Middle Eastern (MID) AF: 0.00431 AC: 1 AN: 232

European-Non Finnish (NFE) AF: 0.00221 AC: 126 AN: 57078

Other (OTH) AF: 0.00706 AC: 12 AN: 1700

Alfa AF: 0.000709 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;