chr7-141662687-A-G

Position:

• chr7-141662687-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080392.2(DENND11):​c.1337T>C​(p.Met446Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000483 in 1,450,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DENND11 NM_001080392.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

Genes affected

DENND11 (HGNC:29472): (DENN domain containing 11) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2351602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND11	NM_001080392.2	c.1337T>C	p.Met446Thr	missense_variant	9/9	ENST00000536163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND11	ENST00000536163.6	c.1337T>C	p.Met446Thr	missense_variant	9/9	1	NM_001080392.2	P1
DENND11	ENST00000482493.1	c.1025T>C	p.Met342Thr	missense_variant	9/9	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1450702 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 721142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The c.1337T>C (p.M446T) alteration is located in exon 9 (coding exon 9) of the KIAA1147 gene. This alteration results from a T to C substitution at nucleotide position 1337, causing the methionine (M) at amino acid position 446 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.82
Eigen	Benign	-0.062
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.11
Sift	Benign	0.46	T;T
Sift4G	Benign	0.27	T;T
Vest4		0.23
MutPred		0.37		Loss of stability (P = 0.0238);.;
MVP		0.45
MPC		0.34
ClinPred		0.58	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-141362487;