chr7-141664228-C-A

Position:

• chr7-141664228-C-A

Variant summary

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

The NM_001080392.2(DENND11):​c.1116G>T​(p.Leu372Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,431,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DENND11 NM_001080392.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.516

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND11	NM_001080392.2	c.1116G>T	p.Leu372Phe	missense_variant	8/9	ENST00000536163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND11	ENST00000536163.6	c.1116G>T	p.Leu372Phe	missense_variant	8/9	1	NM_001080392.2	P1
DENND11	ENST00000482493.1	c.804G>T	p.Leu268Phe	missense_variant	8/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1431128 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 708608

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: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 10, 2023

The c.1116G>T (p.L372F) alteration is located in exon 8 (coding exon 8) of the KIAA1147 gene. This alteration results from a G to T substitution at nucleotide position 1116, causing the leucine (L) at amino acid position 372 to be replaced by a phenylalanine (F). 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	Benign	0.23
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.037
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T
Sift4G	Uncertain	0.034	D;D
Vest4		0.30
MutPred		0.28		Gain of helix (P = 0.062);.;
MVP		0.34
MPC		0.36
ClinPred		0.90	D
GERP RS		5.2
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -10

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: chr7-141364028;