NM_005921.2:c.11_16dupCGGCGG

Variant names:

• chr5-56815575-T-TGGCGGC
• rs779149827
• NM_005921.2:c.11_16dupCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_005921.2(MAP3K1):​c.11_16dupCGGCGG​(p.Ala4_Ala5dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000523 in 1,146,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: MAP3K1 NM_005921.2 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• Publications: 0 publications found

Genes affected

MAP3K1 (HGNC:6848): (mitogen-activated protein kinase kinase kinase 1) The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

MAP3K1 Gene-Disease associations (from GenCC):

• 46,XY sex reversal 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297204 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005921.2.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005921.2. 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
	MAP3K1	NM_005921.2	MANE Select	c.11_16dupCGGCGG	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 20	NP_005912.1	Q13233

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.11_16dupCGGCGG	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.11_16dupCGGCGG	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.11_16dupCGGCGG	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000523 AC: 6 AN: 1146414 Hom.: 0 Cov.: 31 AF XY: 0.00000722 AC XY: 4 AN XY: 553960

African (AFR) AF: 0.00 AC: 0 AN: 23226

American (AMR) AF: 0.00 AC: 0 AN: 9954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15450

East Asian (EAS) AF: 0.00 AC: 0 AN: 26848

South Asian (SAS) AF: 0.0000253 AC: 1 AN: 39452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3098

European-Non Finnish (NFE) AF: 0.00000313 AC: 3 AN: 958210

Other (OTH) AF: 0.0000435 AC: 2 AN: 45928

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	46,XY sex reversal 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3

Splicing

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

Other links and lift over

dbSNP: rs779149827; hg19: chr5-56111402;