12-32327475-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001714.4(BICD1):c.1020G>T(p.Lys340Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BICD1 NM_001714.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

Genes affected

BICD1 (HGNC:1049): (BICD cargo adaptor 1) This gene encodes an adaptor protein that belongs to the bicaudal D family of dynein cargo adaptors. The encoded protein acts as an intracellular cargo transport cofactor that regulates the microtubule-based loading of cargo onto the dynein motor complex. It also controls dynein motor activity and coordination. It has a domain architecture consisting of coiled-coil domains at the N- and C-termini that are highly conserved in other family members. Naturally occurring mutations in this gene are associated with short telomere length and emphysema. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BICD1	NM_001714.4	c.1020G>T	p.Lys340Asn	missense_variant	5/10	ENST00000652176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BICD1	ENST00000652176.1	c.1020G>T	p.Lys340Asn	missense_variant	5/10		NM_001714.4	A1
BICD1	ENST00000548411.6	c.1020G>T	p.Lys340Asn	missense_variant	5/9	1		P4
BICD1	ENST00000395758.3	c.1020G>T	p.Lys340Asn	missense_variant, NMD_transcript_variant	5/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448664 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718638

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Aug 23, 2021

The c.1020G>T (p.K340N) alteration is located in exon 5 (coding exon 5) of the BICD1 gene. This alteration results from a G to T substitution at nucleotide position 1020, causing the lysine (K) at amino acid position 340 to be replaced by an asparagine (N). 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	Pathogenic	0.74
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;T
Sift4G	Benign	0.13	T;T
Polyphen		0.88	.;P
Vest4		0.80
MutPred		0.61		Loss of ubiquitination at K340 (P = 0.0155);Loss of ubiquitination at K340 (P = 0.0155);
MVP		0.59
MPC		1.1
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1163350046; hg19: chr12-32480409;