NM_005921.2:c.1687-46C>T

Variant names:

• chr5-56874986-C-T
• rs16886448
• NM_005921.2:c.1687-46C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005921.2(MAP3K1):​c.1687-46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAP3K1 NM_005921.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.453
• 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, G2P, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2	c.1687-46C>T		intron_variant	Intron 9 of 19	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.1687-46C>T		intron_variant	Intron 9 of 17		XP_047273174.1
MAP3K1	XM_047417219.1	c.1276-46C>T		intron_variant	Intron 10 of 20		XP_047273175.1
MAP3K1	XM_047417220.1	c.1276-46C>T		intron_variant	Intron 10 of 20		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.1687-46C>T		intron_variant	Intron 9 of 19	1	NM_005921.2	ENSP00000382423.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447478 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 721014

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098968

Other (OTH) AF: 0.00 AC: 0 AN: 59922

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.44
PhyloP100		-0.45

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: rs16886448; hg19: chr5-56170813;