NM_016454.4:c.*368delA

Variant names:

• chr15-34230149-TA-T
• rs566558212
• NM_016454.4:c.*368delA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016454.4(EMC4):​c.*368delA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000048 in 83,386 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: EMC4 NM_016454.4 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 0 publications found

Genes affected

EMC4 (HGNC:28032): (ER membrane protein complex subunit 4) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

SLC12A6 (HGNC:10914): (solute carrier family 12 member 6) This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

SLC12A6 Gene-Disease associations (from GenCC):

• agenesis of the corpus callosum with peripheral neuropathy

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease, axonal, IIa 2II

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016454.4. 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
	EMC4	NM_016454.4	MANE Select	c.*368delA		splice_region	Exon 5 of 5	NP_057538.1	Q5J8M3-1
	SLC12A6	NM_001365088.1	MANE Select	c.*3731delT		3_prime_UTR	Exon 26 of 26	NP_001352017.1	Q9UHW9-1
	EMC4	NM_016454.4	MANE Select	c.*368delA		3_prime_UTR	Exon 5 of 5	NP_057538.1	Q5J8M3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC4	ENST00000267750.9	TSL:1 MANE Select	c.*368delA		splice_region	Exon 5 of 5	ENSP00000267750.4	Q5J8M3-1
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.*3731delT		3_prime_UTR	Exon 26 of 26	ENSP00000346112.3	Q9UHW9-1
	EMC4	ENST00000267750.9	TSL:1 MANE Select	c.*368delA		3_prime_UTR	Exon 5 of 5	ENSP00000267750.4	Q5J8M3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000480 AC: 4 AN: 83386 Hom.: 0 Cov.: 0 AF XY: 0.0000469 AC XY: 2 AN XY: 42648

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

African (AFR) AF: 0.00 AC: 0 AN: 3056

American (AMR) AF: 0.00 AC: 0 AN: 2742

Ashkenazi Jewish (ASJ) AF: 0.000277 AC: 1 AN: 3604

East Asian (EAS) AF: 0.000156 AC: 1 AN: 6400

South Asian (SAS) AF: 0.00 AC: 0 AN: 2002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 434

European-Non Finnish (NFE) AF: 0.0000361 AC: 2 AN: 55396

Other (OTH) AF: 0.00 AC: 0 AN: 5756

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1

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: rs566558212; hg19: chr15-34522350;