5-56815575-T-TGGC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1 PM4_Supporting BP6_Very_Strong BS2

The NM_005921.2(MAP3K1):c.14_16dup(p.Ala5dup) variant causes a 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: MAP3K1 NM_005921.2 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM1: In a initiator_methionine Removed (size 0) in uniprot entity M3K1_HUMAN
• 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 [Benign]. Clinvar id is 1601738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 290 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.14_16dup	p.Ala5dup	inframe_insertion	1/20	ENST00000399503.4
MAP3K1	XM_047417218.1	c.14_16dup	p.Ala5dup	inframe_insertion	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.14_16dup	p.Ala5dup	inframe_insertion	1/20	1	NM_005921.2	P1

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

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

Gnomad4 AFR exome AF: 0.00547

Gnomad4 AMR exome AF: 0.000904

Gnomad4 ASJ exome AF: 0.000388

Gnomad4 EAS exome AF: 0.0000372

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000165

Gnomad4 NFE exome AF: 0.000618

Gnomad4 OTH exome AF: 0.000653

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

Gnomad4 AFR AF: 0.00475

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.000950

Bravo AF: 0.00195

Asia WGS AF: 0.000295 AC: 1 AN: 3408

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

46,XY sex reversal 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs779149827; hg19: chr5-56111402;