chr15-83112799-C-A

Variant names:

• chr15-83112799-C-A
• NM_023003.5:c.95C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_023003.5(TM6SF1):​c.95C>A​(p.Ser32Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,460,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TM6SF1 NM_023003.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40
• Publications: 0 publications found

Genes affected

TM6SF1 (HGNC:11860): (transmembrane 6 superfamily member 1) Predicted to be integral component of membrane. Predicted to be active in lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

HDGFL3 (HGNC:24937): (HDGF like 3) Predicted to enable double-stranded DNA binding activity; microtubule binding activity; and transcription coregulator activity. Predicted to be involved in several processes, including microtubule polymerization; negative regulation of microtubule depolymerization; and neuron projection development. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023003.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM6SF1	NM_023003.5	MANE Select	c.95C>A	p.Ser32Tyr	missense splice_region	Exon 2 of 10	NP_075379.2	Q9BZW5-1
	TM6SF1	NM_001353878.2		c.95C>A	p.Ser32Tyr	missense splice_region	Exon 2 of 11	NP_001340807.1
	TM6SF1	NM_001144903.3		c.95C>A	p.Ser32Tyr	missense splice_region	Exon 2 of 9	NP_001138375.1	Q9BZW5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM6SF1	ENST00000322019.14	TSL:1 MANE Select	c.95C>A	p.Ser32Tyr	missense splice_region	Exon 2 of 10	ENSP00000317000.9	Q9BZW5-1
	TM6SF1	ENST00000565774.5	TSL:1	c.95C>A	p.Ser32Tyr	missense splice_region	Exon 2 of 9	ENSP00000457477.1	Q9BZW5-2
	TM6SF1	ENST00000379390.10	TSL:1	c.95C>A	p.Ser32Tyr	missense splice_region	Exon 2 of 7	ENSP00000368700.6	Q6P4D7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460758 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726778

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110978

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Uncertain	0.011	D
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.34		Loss of sheet (P = 0.0817)
MVP		0.32
MPC		0.80
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.67
Mutation Taster		=151/149	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr15-83781551; COSMIC: COSV99034337; COSMIC: COSV99034337;