NM_005921.2:c.14_16dupCGG

Variant names:

• chr5-56815575-T-TGGC
• rs779149827
• NM_005921.2:c.14_16dupCGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_005921.2(MAP3K1):​c.14_16dupCGG​(p.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 0.000817 in 1,297,762 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: MAP3K1 NM_005921.2 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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 -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005921.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-56815575-T-TGGC is Benign according to our data. Variant chr5-56815575-T-TGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1601738.
• BS2: High AC in GnomAd4 at 290 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.14_16dupCGG	p.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.14_16dupCGG	p.Ala5dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.14_16dupCGG	p.Ala5dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.14_16dupCGG	p.Ala5dup	disruptive_inframe_insertion	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 290 AN: 151240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00476

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00 AC: 0 AN: 6162 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000672 AC: 770 AN: 1146412 Hom.: 2 Cov.: 31 AF XY: 0.000679 AC XY: 376 AN XY: 553958

African (AFR) AF: 0.00547 AC: 127 AN: 23226

American (AMR) AF: 0.000904 AC: 9 AN: 9954

Ashkenazi Jewish (ASJ) AF: 0.000388 AC: 6 AN: 15450

East Asian (EAS) AF: 0.0000372 AC: 1 AN: 26848

South Asian (SAS) AF: 0.00 AC: 0 AN: 39452

European-Finnish (FIN) AF: 0.000165 AC: 4 AN: 24248

Middle Eastern (MID) AF: 0.000323 AC: 1 AN: 3098

European-Non Finnish (NFE) AF: 0.000618 AC: 592 AN: 958208

Other (OTH) AF: 0.000653 AC: 30 AN: 45928

GnomAD4 genome AF: 0.00192 AC: 290 AN: 151350 Hom.: 1 Cov.: 33 AF XY: 0.00195 AC XY: 144 AN XY: 73972

African (AFR) AF: 0.00475 AC: 196 AN: 41290

American (AMR) AF: 0.00105 AC: 16 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3462

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00105 AC: 71 AN: 67766

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00195

Asia WGS AF: 0.000295 AC: 1 AN: 3408

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	46,XY sex reversal 6 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=21/179	disease causing (ClinVar)

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;