2-85362389-T-C

Variant names:

• chr2-85362389-T-C
• rs114287948
• NM_001135022.2:c.129+129T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001135022.2(ELMOD3):​c.129+129T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 677,582 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (15 hom.)
• Consequence: ELMOD3 NM_001135022.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.281
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-85362389-T-C is Benign according to our data. Variant chr2-85362389-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1317741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1886/152114) while in subpopulation AFR AF = 0.0433 (1796/41512). AF 95% confidence interval is 0.0416. There are 45 homozygotes in GnomAd4. There are 880 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 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.129+129T>C		intron	N/A	NP_001128494.1	Q96FG2-1
	ELMOD3	NM_032213.5		c.129+129T>C		intron	N/A	NP_115589.2
	ELMOD3	NM_001135021.2		c.129+129T>C		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.129+129T>C		intron	N/A	ENSP00000387139.3	Q96FG2-1
	ELMOD3	ENST00000315658.11	TSL:1	c.129+129T>C		intron	N/A	ENSP00000318264.7	Q96FG2-6
	ELMOD3	ENST00000393852.8	TSL:1	c.129+129T>C		intron	N/A	ENSP00000377434.4	Q96FG2-1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1881 AN: 151996 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00162 AC: 851 AN: 525468 Hom.: 15 AF XY: 0.00133 AC XY: 375 AN XY: 282418

African (AFR) AF: 0.0435 AC: 628 AN: 14432

American (AMR) AF: 0.00257 AC: 72 AN: 28048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15784

East Asian (EAS) AF: 0.00 AC: 0 AN: 33344

South Asian (SAS) AF: 0.0000561 AC: 3 AN: 53430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45876

Middle Eastern (MID) AF: 0.00142 AC: 5 AN: 3524

European-Non Finnish (NFE) AF: 0.000126 AC: 38 AN: 302360

Other (OTH) AF: 0.00366 AC: 105 AN: 28670

GnomAD4 genome AF: 0.0124 AC: 1886 AN: 152114 Hom.: 45 Cov.: 32 AF XY: 0.0118 AC XY: 880 AN XY: 74360

African (AFR) AF: 0.0433 AC: 1796 AN: 41512

American (AMR) AF: 0.00412 AC: 63 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0126 Hom.: 2

Bravo AF: 0.0146

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.81
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs114287948; hg19: chr2-85589512;