14-50429232-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_006575.6(MAP4K5):c.2193A>G(p.Val731=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,564,206 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: MAP4K5 NM_006575.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.413

Genes affected

MAP4K5 (HGNC:6867): (mitogen-activated protein kinase kinase kinase kinase 5) This gene encodes a member of the serine/threonine protein kinase family, that is highly similar to yeast SPS1/STE20 kinase. Yeast SPS1/STE20 functions near the beginning of the MAP kinase signal cascades that is essential for yeast pheromone response. This kinase was shown to activate Jun kinase in mammalian cells, which suggested a role in stress response. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-50429232-T-C is Benign according to our data. Variant chr14-50429232-T-C is described in ClinVar as [Benign]. Clinvar id is 783688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.413 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K5	NM_006575.6	c.2193A>G	p.Val731=	synonymous_variant	29/33	ENST00000682126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP4K5	ENST00000682126.1	c.2193A>G	p.Val731=	synonymous_variant	29/33		NM_006575.6	P1
MAP4K5	ENST00000013125.9	c.2193A>G	p.Val731=	synonymous_variant	29/33	1		P1
MAP4K5	ENST00000554990.6	n.2946A>G		non_coding_transcript_exon_variant	15/19	2
MAP4K5	ENST00000557390.6	c.*14A>G		3_prime_UTR_variant, NMD_transcript_variant	29/33	3

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2347 AN: 152186 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00358 AC: 651 AN: 181924 Hom.: 14 AF XY: 0.00270 AC XY: 260 AN XY: 96270

Gnomad AFR exome AF: 0.0519

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000423

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00150 AC: 2119 AN: 1411902 Hom.: 51 Cov.: 28 AF XY: 0.00125 AC XY: 872 AN XY: 697850

Gnomad4 AFR exome AF: 0.0519

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000996

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.0155 AC: 2354 AN: 152304 Hom.: 53 Cov.: 32 AF XY: 0.0153 AC XY: 1137 AN XY: 74488

Gnomad4 AFR AF: 0.0530

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00729 Hom.: 8

Bravo AF: 0.0181

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.2
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34382193; hg19: chr14-50895950;