1-44806412-G-A

Position:

• chr1-44806412-G-A

Variant summary

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

The NM_001377534.1(DYNLT4):​c.257C>T​(p.Pro86Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,366,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000022 (0 hom.)
• Consequence: DYNLT4 NM_001377534.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

Genes affected

DYNLT4 (HGNC:32315): (dynein light chain Tctex-type 4) Enables protein phosphatase 1 binding activity. Predicted to be involved in microtubule-based movement. Located in acrosomal vesicle; cytoskeleton; and sperm flagellum. [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=0.071151644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNLT4	NM_001377534.1	c.257C>T	p.Pro86Leu	missense_variant	3/3	ENST00000339355.3	NP_001364463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNLT4	ENST00000339355.3	c.257C>T	p.Pro86Leu	missense_variant	3/3	6	NM_001377534.1	ENSP00000341803.2
DYNLT4	ENST00000675259.1	c.257C>T	p.Pro86Leu	missense_variant	2/2			ENSP00000501642.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1366436 Hom.: 0 Cov.: 32 AF XY: 0.00000296 AC XY: 2 AN XY: 674664

Gnomad4 AFR exome AF: 0.0000351

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: 9.33e-7

Gnomad4 OTH exome AF: 0.0000177

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

Jan 03, 2024

The c.257C>T (p.P86L) alteration is located in exon 2 (coding exon 1) of the TCTEX1D4 gene. This alteration results from a C to T substitution at nucleotide position 257, causing the proline (P) at amino acid position 86 to be replaced by a leucine (L). 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	0.081
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.0080
Sift	Uncertain	0.026	D
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.086
MutPred		0.30		Loss of catalytic residue at P85 (P = 0.0283);
MVP		0.061
ClinPred		0.12	T
GERP RS		1.3
Varity_R		0.038
gMVP		0.27

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: rs1387333969; hg19: chr1-45272084;