Genetic Variant SUN1:p.Asp74His (chr7-838940-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001130965.3(SUN1):c.220G>C(p.Asp74His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D74N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SUN1
NM_001130965.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.557

Publications

0 publications found

Variant links:

Genes affected

SUN1 (HGNC:18587): (Sad1 and UNC84 domain containing 1) This gene is a member of the unc-84 homolog family and encodes a nuclear envelope protein with an Unc84 (SUN) domain. The protein is involved in nuclear anchorage and migration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2019]

SUN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04858592).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130965.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SUN1	NM_001130965.3	MANE Select	c.220G>C	p.Asp74His	missense	Exon 2 of 19	NP_001124437.1
SUN1	NM_001367651.1		c.439G>C	p.Asp147His	missense	Exon 3 of 22	NP_001354580.1
SUN1	NM_001367705.1		c.220G>C	p.Asp74His	missense	Exon 3 of 23	NP_001354634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SUN1	ENST00000401592.6	TSL:1 MANE Select	c.220G>C	p.Asp74His	missense	Exon 2 of 19	ENSP00000384015.1
SUN1	ENST00000457378.6	TSL:1	c.283G>C	p.Asp95His	missense	Exon 4 of 7	ENSP00000395952.2
SUN1	ENST00000405266.5	TSL:5	c.220G>C	p.Asp74His	missense	Exon 2 of 20	ENSP00000384116.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456844

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724238

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

84762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110394

Other (OTH)

AF:

0.00

AC:

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.21

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.0016

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.56

M_CAP

Benign

0.0028

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.51

PhyloP100

-0.56

PrimateAI

Benign

0.41

PROVEAN

Benign

2.2

REVEL

Benign

0.070

Sift

Benign

0.42

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.10

MutPred

0.49

Gain of helix (P = 0.0496)

MVP

0.082

MPC

0.10

ClinPred

0.061

GERP RS

0.27

PromoterAI

0.0078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.19

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over