11-33542633-C-A

Variant names:

• chr11-33542633-C-A
• rs1409255320
• NM_012194.3:c.1070C>A

Variant summary

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

The NM_012194.3(KIAA1549L):​c.1070C>A​(p.Pro357His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000014 (0 hom.)
• Consequence: KIAA1549L NM_012194.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.176

Genes affected

KIAA1549L (HGNC:24836): (KIAA1549 like) Predicted to be integral component of membrane. [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=0.078437686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA1549L	NM_012194.3	c.1070C>A	p.Pro357His	missense_variant	Exon 2 of 21	ENST00000658780.2	NP_036326.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA1549L	ENST00000658780.2	c.1070C>A	p.Pro357His	missense_variant	Exon 2 of 21		NM_012194.3	ENSP00000499430.1
KIAA1549L	ENST00000321505.9	c.179C>A	p.Pro60His	missense_variant	Exon 1 of 20	1		ENSP00000315295.4
KIAA1549L	ENST00000265654.6	c.302C>A	p.Pro101His	missense_variant	Exon 1 of 11	2		ENSP00000265654.6
KIAA1549L	ENST00000526400.7	c.583+487C>A		intron_variant	Intron 2 of 20	5		ENSP00000433481.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461572 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727068

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179C>A (p.P60H) alteration is located in exon 1 (coding exon 1) of the KIAA1549L gene. This alteration results from a C to A substitution at nucleotide position 179, causing the proline (P) at amino acid position 60 to be replaced by a histidine (H). 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	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.24	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.030
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		0.017	.;B
Vest4		0.20
MutPred		0.25		Loss of glycosylation at P60 (P = 0.0016);Loss of glycosylation at P60 (P = 0.0016);
MVP		0.048
MPC		0.44
ClinPred		0.16	T
GERP RS		1.7
Varity_R		0.057
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1409255320; hg19: chr11-33564179;