4-76754772-G-A

Variant names:

• chr4-76754772-G-A
• rs61741104
• NM_020859.4:c.4289G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020859.4(SHROOM3):​c.4289G>A​(p.Arg1430Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,614,086 control chromosomes in the GnomAD database, including 2,287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (193 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2094 hom.)
• Consequence: SHROOM3 NM_020859.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.799
• Publications: 7 publications found

Genes affected

SHROOM3 (HGNC:30422): (shroom family member 3) This gene encodes a PDZ-domain-containing protein that belongs to a family of Shroom-related proteins. This protein may be involved in regulating cell shape in certain tissues. A similar protein in mice is required for proper neurulation. [provided by RefSeq, Jan 2011]

SHROOM3-AS1 (HGNC:41265): (SHROOM3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017259121).
• BP6: Variant 4-76754772-G-A is Benign according to our data. Variant chr4-76754772-G-A is described in ClinVar as Benign. ClinVar VariationId is 403442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM3	NM_020859.4	MANE Select	c.4289G>A	p.Arg1430Gln	missense	Exon 7 of 11	NP_065910.3
	SHROOM3-AS1	NR_187404.1		n.951+3277C>T		intron	N/A
	SHROOM3-AS1	NR_187405.1		n.408-11872C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM3	ENST00000296043.7	TSL:1 MANE Select	c.4289G>A	p.Arg1430Gln	missense	Exon 7 of 11	ENSP00000296043.6
	SHROOM3	ENST00000646790.1		c.4046G>A	p.Arg1349Gln	missense	Exon 6 of 10	ENSP00000494970.1
	SHROOM3-AS1	ENST00000660459.1		n.371-44378C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5571 AN: 152142 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.00985

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0996

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0546

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0498 AC: 12506 AN: 251020 AF XY: 0.0486

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0435

Gnomad OTH exome AF: 0.0519

GnomAD4 exome AF: 0.0479 AC: 69968 AN: 1461826 Hom.: 2094 Cov.: 74 AF XY: 0.0478 AC XY: 34752 AN XY: 727212

African (AFR) AF: 0.00797 AC: 267 AN: 33480

American (AMR) AF: 0.124 AC: 5564 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0572 AC: 1496 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0586 AC: 5051 AN: 86250

European-Finnish (FIN) AF: 0.0103 AC: 551 AN: 53416

Middle Eastern (MID) AF: 0.0428 AC: 247 AN: 5768

European-Non Finnish (NFE) AF: 0.0485 AC: 53953 AN: 1111980

Other (OTH) AF: 0.0469 AC: 2831 AN: 60396

GnomAD4 genome AF: 0.0367 AC: 5583 AN: 152260 Hom.: 193 Cov.: 32 AF XY: 0.0374 AC XY: 2787 AN XY: 74452

African (AFR) AF: 0.00982 AC: 408 AN: 41546

American (AMR) AF: 0.100 AC: 1531 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4828

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0435 AC: 2959 AN: 67998

Other (OTH) AF: 0.0468 AC: 99 AN: 2116

Alfa AF: 0.0411 Hom.: 509

Bravo AF: 0.0424

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0428 AC: 165

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0449 AC: 386

ExAC AF: 0.0451 AC: 5472

Asia WGS AF: 0.0260 AC: 93 AN: 3478

EpiCase AF: 0.0493

EpiControl AF: 0.0503

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	SHROOM3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.2
DANN	Benign	0.84
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.80
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.015
Sift	Benign	0.37	T
Sift4G	Benign	0.60	T
Polyphen		0.0040	B
Vest4		0.037
MPC		0.36
ClinPred		0.00088	T
GERP RS		1.9
Varity_R		0.023
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61741104; hg19: chr4-77675925;